Kyushu University Academic Staff Educational and Research Activities Database
Researcher information (To researchers) Need Help? How to update
Satohiro Masuda Last modified date:2018.06.28

Professor / Department of Pharmacy
Pharmacy
Kyushu University Hospital


Graduate School
Undergraduate School


E-Mail
Academic Degree
Ph.D.
Field of Specialization
Pharmacotherapy, Clinical Pharmacology, Drug Pharmacokinetics and Toxicology
Research
Research Interests
  • Establishment of countermeasure methodology against drug-induced organ toxicity based on clarification of molecular mechanism
    keyword : adverse reactions, drug transporter, drug metabolism enzyme, receptor, phosphorylation
    2010.04.
  • Establishment of e personalized dosage adjustment of immunosuppressive agents
    keyword : liver transplantation, kidney transplantation, ulcerative colitis, Crohn's disease, calcineurin inhibitor, mTOR inhibitor, Therapeutic Drug Monitoring (TDM), genetic polymorphism
    1999.11.
  • Exploration and clinical application of biomarkers associated with drug-related organ injury
    keyword : urinary biomarker, serum biomarker, SiRNA, metabolomics
    2007.06.
  • study on molecular mechanisms in drug-induced nephrotoxicity
    keyword : drug transporter, acute kidney injury
    1997.04.
Current and Past Project
  • http://www.jsps.go.jp/english/e-jisedai/data/life/LR014_e-outline.pdf
Academic Activities
Reports
1. Shipkova M, Hesselink DA, Holt DW, Billaud EM, van Gelder T, Kunicki PK, Brunet M, Budde K, Barten MJ, De Simone P, Wieland E, Lopez OM, 増田 智先, Seger C, Picard N, Oellerich M, Langman LJ, Wallemacq P, Morris RG, Therapeutic Drug Monitoring of Everolimus: A Consensus Report. , Therapeutic drug monitoring, 38(2)143-69, 2016.04.
Papers
1. Yamamoto, S., S. Ushio, N. Egashira, T. Kawashiri, S. Mitsuyasu, H. Higuchi, N. Ozawa, K. Masuguchi, Y. Ono and S. Masuda., Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: a possibility for riluzole as a prophylactic drug., SCIENTIFIC REPORTS , 10.1038/s41598-017-08891-1 , 7, 9661, 2017.08, Oxaliplatin, a chemotherapy medication, causes severe peripheral neuropathy. Although oxaliplatin-induced peripheral neuropathy is a dose-limiting toxicity, a therapeutic strategy against its effects has not been established. We previously reported the involvement of N-methyl-D-aspartate receptors and their intracellular signalling pathway in oxaliplatin-induced mechanical allodynia in rats. The aim of this study was to clarify the involvement of spinal glutamate transmission in oxaliplatin-induced mechanical allodynia. In vivo spinal microdialysis revealed that the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation of the hind paw markedly increased extracellular glutamate concentration in the same rats. In these rats, the expression of glutamate transporter 1 (GLT-1), which plays a major role in glutamate uptake, was decreased in the spinal cord. Moreover, we explored the potential of pharmacological therapy targeting maintenance of extracellular glutamate homeostasis. The administration of riluzole, an approved drug for amyotrophic lateral sclerosis, suppressed the increase of glutamate concentration, the decrease of GLT-1 expression and the development of mechanical allodynia. These results suggest that oxaliplatin disrupts the extracellular glutamate homeostasis in the spinal cord, which may result in neuropathic symptoms, and support the use of riluzole for prophylaxis of oxaliplatin-induced mechanical allodynia..
2. Yamada, T., T. Kubota, M. Yonezawa, H. Nishio, S. Kanno, T. Yano, D. Kobayashi, N. Egashira, H. Takada, T. Hara and S. Masuda., Evaluation of Teicoplanin Trough Values After the Recommended Loading Dose in Children With Associated Safety Analysis., PEDIATRIC INFECTIOUS DISEASE JOURNAL , 10.1097/INF.0000000000001456, 36, 4, 398-400, 2017.04, Background: This study evaluated whether the recommended teicoplanin loading dose (3 loading doses of 10 mg/kg every 12 hours) achieves a 15-30 mu g/mL trough levels in 26 children (2-16 years). In addition, we examined the incidences of renal impairment and hepatic dysfunction in children treated with teicoplanin.

Methods: This retrospective study was conducted between October 2008 and March 2014.

Results: The percentage of patients with a trough level <10 and <15 mu g/mL were 15.4% (4/26) and 46.2% (12/26), respectively. There were significant correlations between age and concentration/cumulative loading dose (C/D) ratio (P = 0.045), serum creatinine and C/D ratio (P < 0.001) and estimated glomerular filtration rate and C/D ratio (P = 0.005). Serum creatinine was significantly lower when trough levels were < 15 mu g/mL compared with >= 15 mu g/mL. The incidences of renal impairment and hepatic dysfunction were 2.3% and 5.8%, respectively, with no significant difference between < 20 and >= 20 mu g/mL trough-level groups.

Conclusions: The recommended loading dose may be insufficient to achieve 15-30 mu g/mL in children with normal renal function. In addition, the target trough level >= 20 mu g/mL for deep-seated infections seems to be safe in children..
3. Suetsugu, K., H. Ikesue, T. Miyamoto, M. Shiratsuchi, N. Yamamoto-Taguchi, Y. Tsuchiya, K. Matsukawa, M. Uchida, H. Watanabe, K. Akashi and S. Masuda., Analysis of the variable factors influencing tacrolimus blood concentration during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation., INTERNATIONAL JOURNAL OF HEMATOLOGY , 10.1007/s12185-016-2135-7, 105, 3, 361-368, 2017.03, The aim of this retrospective study was to identify variable factors affecting tacrolimus blood concentration during the switch from continuous intravenous infusion to twice-daily oral administration in allogeneic hematopoietic stem cell transplant recipients (n = 73). The blood concentration/dose ratio of tacrolimus immediately before the change from continuous infusion (C/Div) was compared with that between 3 and 5 days after the change to oral administration (C/Dpo). Median (C/Dpo)/(C/Div) was 0.21 (range 0.04-0.58). Multiple regression analysis showed that concomitant use of oral itraconazole or voriconazole significantly increased the (C/Dpo)/(C/Div) of tacrolimus (p = 0.002), probably owing to the inhibition of enterohepatic cytochrome P450 3A4. In addition, 5 of 18 (28%) patients who had the lowest quartile (C/Dpo)/(C/Div) values developed acute graft-versus-host-disease (GVHD), which was significantly higher than in others [5 of 55 (9%) patients, p = 0.045]. Although the switch from intravenous to oral administration at a ratio of 1:5 appeared to be appropriate, a lower conversion ratio was suitable in patients taking oral itraconazole or voriconazole. In patients whose blood concentration decreases after the switch, the development of GVHD should be monitored and tacrolimus dosage should be readjusted to maintain an appropriate blood concentration..
4. Sakamoto, Y ; Yano, T ; Hanada, Y; Takeshita, A; Inagaki, F; Masuda, S; Matsunaga, N ; Koyanagi, S ; Ohdo, S ., Vancomycin induces reactive oxygen species-dependent apoptosis via mitochondrial cardiolipin peroxidation in renal tubular epithelial cells, EUROPEAN JOURNAL OF PHARMACOLOGY, 10.1016/j.ejphar.2017.02.025, 800, 48-56, 2017.05, Vancomycin (VCM) is a first-line antibiotic for serious infections caused by methicillin-resistant Staphylococcus aureus. However, nephrotoxicity is one of the most complaint in VCM therapy. We previously reported that VCM induced apoptosis in a porcine proximal tubular epithelial cell line (LLC-PK1), in which mitochondrial complex I may generate superoxide, leading to cell death. In the present study, VCM caused production of mitochondrial reactive oxygen species and peroxidation of the mitochondrial phospholipid cardiolipin that was reversed by administration of the mitochondrial uncoupler carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP). FCCP also significantly suppressed VCM-induced depolarization of the mitochondrial membrane and apoptosis. Moreover, the lipophilic antioxidant vitamin E and a mitochondria-targeted antioxidant, mitoTEMPO, also significantly suppressed VCM-induced depolarization of mitochondrial membrane and apoptosis, whereas vitamin C, n-acetyl cysteine, or glutathione did not provide significant protection. These findings suggest that peroxidation of the mitochondrial membrane cardiolipin mediated the VCM-induced production of intracellular reactive oxygen species and initiation of apoptosis in LLC-PK1 cells. Furthermore, regulation of mitochondrial function using a mitochondria-targeted antioxidant, such as mitoTEMPO, may constitute a potential strategy for mitigation of VCM-induced proximal tubular epithelial cell injury..
5. Murata, K., Y. Motomura, T. Tanaka, S. Kanno, T. Yano, M. Onimaru, A. Shimoyama, H. Nishio, Y. Sakai, M. Oh-Hora, H. Hara, K. Fukase, H. Takada, S. Masuda, S. Ohga, S. Yamasaki and T. Hara., Calcineurin inhibitors exacerbate coronary arteritis via the MyD88 signaling pathway in a murine model of Kawasaki disease., Clin Exp Immunol, 10.1111/cei.13002 , 190, 1, 54-67, 2017.10, Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice. We also performed in-vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9(-/-) mice but not in MyD88(-/-) mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD..
6. Yoshimatsu, Hiroki, Yonezawa, Atsushi, Yamanishi, Kaori, Yao, Yoshiaki, Sugano, Kumiko, Nakagawa, Shunsaku, Imai, Satoshi, Omura, Tomohiro, Nakagawa, Takayuki, Yano, Ikuko, Satohiro Masuda, Inui, Ken-ichi, Matsubara, Kazuo, Disruption of Slc52a3 gene causes neonatal lethality with riboflavin deficiency in mice, Scientific reports, 10.1038/srep27557, 6, 2016.06, Homeostasis of riboflavin should be maintained by transporters. Previous in vitro studies have elucidated basic information about riboflavin transporter RFVT3 encoded by SLC52A3 gene. However, the contribution of RFVT3 to the maintenance of riboflavin homeostasis and the significance in vivo remain unclear. Here, we investigated the physiological role of RFVT3 using Slc52a3 knockout (Slc52a3-/-) mice. Most Slc52a3-/- mice died with hyperlipidemia and hypoglycemia within 48 hr after birth. The plasma and tissue riboflavin concentrations in Slc52a3-/- mice at postnatal day 0 were dramatically lower than those in wild-type (WT) littermates. Slc52a3-/- fetuses showed a lower capacity of placental riboflavin transport compared with WT fetuses. Riboflavin supplement during pregnancy and after birth reduced neonatal death and metabolic disorders. To our knowledge, this is the first report to indicate that Rfvt3 contributes to placental riboflavin transport, and that disruption of Slc52a3 gene caused neonatal mortality with hyperlipidemia and hypoglycemia owing to riboflavin deficiency..
7. Yamada, Takaaki, Ueda, Mitsuyo, Egashira, Nobuaki, Zukeyama, Nina, Kuwahara, Jun, Satohiro Masuda, Involvement of intracellular cAMP in epirubicin-induced vascular endothelial cell injury, Journal of pharmacological sciences, 10.1016/j.jphs.2015.12.010, 130, 1, 33-37, 2016.01, We investigated the involvement of intracellular cAMP in endothelial cell injury induced by epirubicin. Epirubicin-induced decrease in cell viability and increase in caspase-3/7 activity were reversed by a cAMP analog dibutyryl cAMP (DBcAMP) or an activator of adenylate cyclase forskolin concomitant with a phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Moreover, epirubicin-induced elevation of lipid peroxide levels was attenuated by DBcAMP. Interestingly, the exposure of epirubicin decreased intracellular cAMP levels before the onset of epirubicin-induced production of lipid peroxidation. These results suggest that intracellular cAMP plays an important role in epirubicin-induced endothelial cell injury..
8. Yahata, Hideaki, Kobayashi, Hiroaki, Sonoda, Kenzo, Shimokawa, Mototsugu, Ohgami, Tatsuhiro, Saito, Toshiaki, Ogawa, Shinji, Sakai, Kunihiro, Ichinoe, Akimasa, Ueoka, Yousuke, Hasuo, Yasuyuki, Nishida, Makoto, Satohiro Masuda, Kato, Kiyoko, Efficacy of aprepitant for the prevention of chemotherapy-induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: a multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving paclitaxel and carboplatin, INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 10.1007/s10147-015-0928-y, 21, 3, 491-497, 2016.06, BACKGROUND: Substance P contributes to the hypersensitivity reaction (HSR) to paclitaxel in a rat model. Aprepitant acts as an inhibitor of the binding of substance P to the neurokinin-1 receptor and, consequently, may reduce the frequency of paclitaxel-induced HSR. While aprepitant has a prophylactic effect against vomiting caused by high-dose cisplatin, the benefits of aprepitant have not been clearly demonstrated in patients receiving paclitaxel and carboplatin (TC) combination chemotherapy. METHODS: We conducted a multicenter, placebo-controlled, double-blind, randomized study in Japanese patients with gynecologic cancer who received TC combination chemotherapy. Patients received aprepitant or placebo together with both a 5-HT3 receptor antagonist and dexamethasone prior to chemotherapy. The primary endpoint was the proportion of patients with HSR, and the secondary endpoints were the proportion of patients with "no vomiting", "no significant nausea", and complete response, respectively. RESULTS: Of the 324 randomized patients, 297 (151 in the aprepitant group; 146 in the placebo group) were evaluated. The percentage of patients with HSR (9.2 vs. 7.5 %, respectively; P = 0.339) was not significantly different between the groups. The percentage of "no vomiting" patients (78.2 vs. 54.8 %; P < 0.0001), "no significant nausea" patients (85.4 vs. 74.7 %; P = 0.014), and patients showing complete response (61.6 vs. 47.3 %, P = 0.0073) was significantly higher in the aprepitant group than in the placebo group. CONCLUSION: The administration of aprepitant did not have a prophylactic effect on the HSR but was effective in reducing nausea and vomiting in gynecologic cancer patients receiving TC combination chemotherapy..
9. Tanaka, Satona, Chen-Yoshikawa, Toyofumi F, Kajiwara, Moto, Menju, Toshi, Ohata, Keiji, Takahashi, Mamoru, Kondo, Takeshi, Hijiya, Kyoko, Motoyama, Hideki, Aoyama, Akihiro, Satohiro Masuda, Date, Hiroshi, Protective Effects of Imatinib on Ischemia/Reperfusion Injury in Rat Lung, ANNALS OF THORACIC SURGERY, 10.1016/j.athoracsur.2016.05.037, 102, 5, 1717-1724, 2016.11, PURPOSE: Docetaxel is frequently used in the treatment of a wide variety of solid tumors, including breast cancer. The aim of this study is to obtain the population pharmacokinetic parameters of docetaxel in Japanese female patients with breast cancer. METHODS: Blood samples from 24 patients were collected sequentially before and after docetaxel infusion. Genomic DNA was isolated from the peripheral blood and genotyped for the selected polymorphisms in the candidate genes of drug transporters and metabolizing enzymes. The influence of patient characteristics on the pharmacokinetics of docetaxel was evaluated using the nonlinear-mixed-effect modeling program, NONMEM. As a basis for comparison, the pharmacokinetics of another taxane paclitaxel in 41 separate female patients with breast cancer was calculated. RESULTS: A two-compartment model adequately described the pharmacokinetic profiles of docetaxel. The population mean estimates of the total body clearance for patients aged 58 years or less and the central volume of distribution for docetaxel were 32.6 L/h and 5.77 L, respectively. In patients over 58 years, the clearance was 24 % higher than that in the younger patients. No influences of the genotypes examined were noted on the clearance of docetaxel. The clearance of paclitaxel was not affected by patient age. CONCLUSIONS: Patients over the age of 58 years showed significantly higher clearance of docetaxel than that in patients aged 58 years or less. Since the clearance of paclitaxel was not affected by the age, it is possible that the pharmacokinetic mechanisms of docetaxel might be specifically affected by age in females..
10. Shipkova, Maria, Hesselink, Dennis A, Holt, David W, Billaud, Eliane M, van Gelder, Teun, Kunicki, Pawel K, Brunet, Merce, Budde, Klemens, Barten, Markus J, De Simone, Paolo, Wieland, Eberhard, Millan Lopez, Olga, Satohiro Masuda, Seger, Christoph, Picard, Nicolas, Oellerich, Michael, Langman, Loralie J, Morris, Raymond G, Thompson, Carol, Therapeutic Drug Monitoring of Everolimus: A Consensus Report, THERAPEUTIC DRUG MONITORING, 38, 2, 143-169, 2016.04, PURPOSE: Docetaxel is frequently used in the treatment of a wide variety of solid tumors, including breast cancer. The aim of this study is to obtain the population pharmacokinetic parameters of docetaxel in Japanese female patients with breast cancer. METHODS: Blood samples from 24 patients were collected sequentially before and after docetaxel infusion. Genomic DNA was isolated from the peripheral blood and genotyped for the selected polymorphisms in the candidate genes of drug transporters and metabolizing enzymes. The influence of patient characteristics on the pharmacokinetics of docetaxel was evaluated using the nonlinear-mixed-effect modeling program, NONMEM. As a basis for comparison, the pharmacokinetics of another taxane paclitaxel in 41 separate female patients with breast cancer was calculated. RESULTS: A two-compartment model adequately described the pharmacokinetic profiles of docetaxel. The population mean estimates of the total body clearance for patients aged 58 years or less and the central volume of distribution for docetaxel were 32.6 L/h and 5.77 L, respectively. In patients over 58 years, the clearance was 24 % higher than that in the younger patients. No influences of the genotypes examined were noted on the clearance of docetaxel. The clearance of paclitaxel was not affected by patient age. CONCLUSIONS: Patients over the age of 58 years showed significantly higher clearance of docetaxel than that in patients aged 58 years or less. Since the clearance of paclitaxel was not affected by the age, it is possible that the pharmacokinetic mechanisms of docetaxel might be specifically affected by age in females..
11. Onoue, Haruka, Yano, Ikuko, Tanaka, Atsuko, Itohara, Kotaro, Hanai, Akiko, Ishiguro, Hiroshi, Motohashi, Hideyuki, Satohiro Masuda, Matsubara, Kazuo, Significant effect of age on docetaxel pharmacokinetics in Japanese female breast cancer patients by using the population modeling approach, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 10.1007/s00228-016-2031-3, 72, 6, 703-710, 2016.06, PURPOSE: Docetaxel is frequently used in the treatment of a wide variety of solid tumors, including breast cancer. The aim of this study is to obtain the population pharmacokinetic parameters of docetaxel in Japanese female patients with breast cancer. METHODS: Blood samples from 24 patients were collected sequentially before and after docetaxel infusion. Genomic DNA was isolated from the peripheral blood and genotyped for the selected polymorphisms in the candidate genes of drug transporters and metabolizing enzymes. The influence of patient characteristics on the pharmacokinetics of docetaxel was evaluated using the nonlinear-mixed-effect modeling program, NONMEM. As a basis for comparison, the pharmacokinetics of another taxane paclitaxel in 41 separate female patients with breast cancer was calculated. RESULTS: A two-compartment model adequately described the pharmacokinetic profiles of docetaxel. The population mean estimates of the total body clearance for patients aged 58 years or less and the central volume of distribution for docetaxel were 32.6 L/h and 5.77 L, respectively. In patients over 58 years, the clearance was 24 % higher than that in the younger patients. No influences of the genotypes examined were noted on the clearance of docetaxel. The clearance of paclitaxel was not affected by patient age. CONCLUSIONS: Patients over the age of 58 years showed significantly higher clearance of docetaxel than that in patients aged 58 years or less. Since the clearance of paclitaxel was not affected by the age, it is possible that the pharmacokinetic mechanisms of docetaxel might be specifically affected by age in females..
12. Miura, M, Satohiro Masuda, Egawa, H., Yuzawa, K, Matsubara, K, Inter-laboratory Variability of Current Immunoassay Methods for Tacrolimus Among Japanese Hospitals, Biological & pharmaceutical bulletin, 10.1248/bpb.b16-00249, 39, 8, 1331-1337, 2016.06.
13. Mio Kikuchi, Yuki Okuda, Yoshihide Ueda, Yuki Nishioka, Miwa Uesugi, Emina Hashimoto, Tamotsu Takahashi, Tomoki Kawai, Sachiyo Hashi, Haruka Shinke, Tomohiro Omura, Atsushi Yonezawa, Takashi Ito, Yasuhiro Fujimoto, Toshimi Kaido, Tsutomu Chiba, Shinji Uemoto, Kazuo Matsubara, Satohiro Masuda, Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients, 37, 3, 417-423, 2014.03, Telaprevir (TVR) is a protease inhibitor used in combination with pegylated interferon alfa-2b and ribavirin for hepatitis C, and TVR strongly inhibits CYP3A4 and CYP3A5. We reported successful TVR treatment of liver transplant patients with recurrence of hepatitis C during receiving immunosuppressive therapy. Before initiation of triple therapy, all patients switched from tacrolimus to cyclosporine, which has a lower inhibitory effect on CYP3A4 and CYP3A5 than tacrolimus. To avoid graft failure, we measured the cyclosporine blood concentrations at 0, 2, and 6 h after administration to maintain the target level (150-200 ng/mL) within 1 week after initiation of TVR and adjusted the dose of cyclosporine. The dose of cyclosporine was decreased 0.24-0.40 fold in all patients after initiation of TVR treatment. In 3 patients, the dose of TVR was decreased two-thirds of starting dose because of adverse effects, including anorexia and skin rash. However, the HCV RNA level rapidly decreased to undetectable levels within 1 month. Furthermore, all patients completed the TVR therapy in 12 weeks and did not experience liver graft rejection. In addition, we found the rapid elimination of inhibitory effect of TVR on the disposition of cyclospirne in the all four cases and therefore, rapid increase in the dosage of cyclosporine would be required immediately after the end of TVR administration. These results suggest that frequent measurement of cyclosporine levels was important for successful TVR triple therapy and prevention of rejection..
14. Ayami Tsuchimoto, Haruka SHinke, Miwa Uesugi, Mio Kikuchi, Emina Hashimoto, Tomoko Sato, Yasuhiro Ogura, Koichiro Hata, Yasuhiro Fujimoto, Toshimi Kaido, Junji Kishimoto, Motoko Yanagita, Kazuo Matsubara, Shinji Uemoto, Satohiro Masuda, Urinary neutrophil gelatinase-associated lipocalin: a useful biomarker for tacrolimus-induced acute kidney injury in liver transplant patients, PLoS ONE, 10.1371/journal.pone.0110527, 9, 10, e110527, 2014.10, Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication of liver transplantation. For early detection of AKI, various urinary biomarkers such as monocyte chemotactic protein-1, liver-type fatty acid-binding protein, interleukin-18, osteopontin, cystatin C, clusterin and neutrophil gelatinase-associated lipocalin (NGAL) have been identified. Here, we attempt to identify urinary biomarkers for the early detection of tacrolimus-induced AKI in liver transplant patients. Urine samples were collected from 31 patients after living-donor liver transplantation (LDLT). Twenty recipients developed tacrolimus-induced AKI. After the initiation of tacrolimus therapy, urine samples were collected on postoperative days 7, 14, and 21. In patients who experienced AKI during postoperative day 21, additional spot urine samples were collected on postoperative days 28, 35, 42, 49, and 58. The 8 healthy volunteers, whose renal and liver functions were normal, were asked to collect their blood and spot urine samples. The urinary levels of NGAL, monocyte chemotactic protein-1 and liver-type fatty acid-binding protein were significantly higher in patients with AKI than in those without, while those of interleukin-18, osteopontin, cystatin C and clusterin did not differ between the 2 groups. The area under the receiver operating characteristics curve of urinary NGAL was 0.876 (95% confidence interval, 0.800-0.951; P<0.0001), which was better than those of the other six urinary biomarkers. In addition, the urinary levels of NGAL at postoperative day 1 (p = 0.0446) and day 7 (p = 0.0006) can be a good predictive marker for tacrolimus-induced AKI within next 6 days, respectively. In conclusion, urinary NGAL is a sensitive biomarker for tacrolimus-induced AKI, and may help predict renal event caused by tacrolimus therapy in liver transplant patients..
15. Miwa Uesugi, Mio Kikuchi, Haruka Shinke, Tomohiro Omura, Atsushi Yonezawa, Kazuo Matsubara, Yasuhiro Fujimoto, Shinya Okamoto, Toshimi Kaido, Shinji Uemoto, Satohiro Masuda, Impact of cytochrome P450 3A5 polymorphism in graft livers on the frequency of acute cellular rejection in living-donor liver transplantation, Pharmacogenetics and Genomics, 10.1097/fpc.0000000000000060, 24, 7, 356-366, 2014.07, OBJECTIVE: We investigated whether the cytochrome P450 3A5*3 (CYP3A5*3) genotype affects tacrolimus pharmacokinetics and the risk of acute cellular rejection in living-donor liver transplant patients in Japan.
MATERIALS AND METHODS:
Between July 2004 and June 2011, we enrolled 410 living-donor liver transplant patients receiving tacrolimus. Biopsy specimens of intestinal mucosa and graft liver at surgery were obtained to examine the mRNA expression of CYP3A subfamilies as well as the genotyping of CYP3A5*3 polymorphism.
RESULTS:
The CYP3A5 genotype in the native intestine had no significant effect on the occurrence of acute cellular rejection between postoperative days 14 and 23 in cases with identical or compatible ABO blood types (11.5% for the CYP3A5*1 allele vs. 7.4% for CYP3A5*3/*3; P=0.2643), although the concentration/dose ratio of tacrolimus was significantly higher in patients with the intestinal CYP3A5*3/*3 genotype than in those with the CYP3A5*1 allele for 5 post-transplant weeks. However, patients who received a graft liver with the CYP3A5*1 allele showed a higher rate of acute cellular rejection than those who received a graft liver with the CYP3A5*3/*3 genotype (14.5 vs. 5.7%; P=0.0134). The relative risk for acute cellular rejection associated with the CYP3A5*1 liver allele was 2.629 (P=0.018, Cox regression model). Consequently, graft liver CYP3A5*1 genotype might increase the risk for acute cellular rejection after living-donor liver transplantation, possibly by associating with the local hepatic tacrolimus concentration.
CONCLUSIONS:
The target level of tacrolimus may be affected by the CYP3A5*3 genotype of the liver, rather than by that of the small intestine, after postoperative day 14..
16. Takaaki Kodawara, Satohiro Masuda, Yoshitaka Yano, Kazuo Matsubara, Toshiaki Nakamura, Mikio Masada, Inhibitory effect of ciprofloxacin on β-glucuronidase-mediated deconjugation of mycophenolic acid glucuronide, Biopharm Drug Dispos, 10.10022/bdd1894, 2014.05, The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, we established an in vitro system to evaluate β-glucuronidase-mediated deconjugation and examined the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time-dependent manner from 5 to 60 min in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-D-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β-glucuronidase-mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose-dependent inhibitory effect on MPA production from MPAG via β-glucuronidase with a half-maximal inhibitory concentration (IC50) value of 30.4 µM. While PhePG inhibited the β-glucuronidase-mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that reduction in the serum MPA concentration during the co-administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β-glucuronidase..
17. Sachiyo Hashi, Satohiro Masuda, Mio Kikuchi, Miwa Uesugi, Ikuko Yano, Tomohiro Omura, Atsushi Yonezawa, Yasuhiro Fujimoto, Kohei Ogawa, Toshimi Kaido, Shinji Uemoto, Kazuo Matsubara, Assessment of Four Methodologies (Microparticle Enzyme Immunoassay, Chemiluminescent Enzyme Immunoassay, Affinity Column-Mediated Immunoassay, and Flow Injection Assay-Tandem Mass Spectrometry) for Measuring Tacrolimus Blood Concentration in Japanese Liver Transplant Recipients, TRANSPLANTATION PROCEEDINGS, 10.1016/j.transproceed.2013.11.060, 46, 3, 758-760, 2014.04, Therapeutic drug monitoring (TDM) and subsequent dosage adjustment for individual patients in the treatment with tacrolimus are required after liver transplantation to prevent rejection and over-immunosuppression, which leads to severe infection and adverse reactions including nephrotoxicity. The purpose of this study was to evaluate the analytical performance among commercially available immunoassay methods, which were microparticle enzyme immunoassay (MEIA), chemiluminescent enzyme immunoassay (CLIA), and affinity column-mediated immunoassay (ACMIA), compared with an assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, the flow injection assay (FIA-MS/MS) was also evaluated to determine whether it could be available as a new method of analysis in tacrolimus therapy. The blood tacrolimus concentrations in samples from liver transplant recipients (n = 102) were measured using MEIA, CLIA, ACMIA, and LC-MS/MS. Additional blood samples from liver transplant recipients (n = 54) were analyzed using both FIA-MS/MS and LC-MS/MS. Because the assay performance and characteristics of MEIA, CLIA, ACMIA, and FIA-MS/MS are relatively different, the measured data should be carefully considered depending on the methodology..
18. Mio Kikuchi, Yuki Okuda, Yoshihide Ueda, Yuki Nishioka, Miwa Uesugi, Emina Hashimoto, Tamotsu Hashimoto, Tomoki Kawai, Sachiyo Hashi, Haruka Shinke, Tomohiro Omura, Atsushi Yonezawa, Takashi Ito, Yasuhiro Fujimoto, Toshimi Kaido, Tsutomu Chiba, Shinji Uemoto, Kazuo Matsubara, Satohiro Masuda, Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 37, 3, 417-423, 2014.03, Telaprevir (TVR) is a protease inhibitor used in combination with pegylated interferon alfa-2b and ribavirin for hepatitis C, and TVR strongly inhibits CYP3A4 and CYP3A5. We reported successful TVR treatment of liver transplant patients with recurrence of hepatitis C during receiving immunosuppressive therapy. Before initiation of triple therapy, all patients switched from tacrolimus to cyclosporine, which has a lower inhibitory effect on CYP3A4 and CYP3A5 than tacrolimus. To avoid graft failure, we measured the cyclosporine blood concentrations at 0, 2, and 6 h after administration to maintain the target level (150-200 ng/mL) within 1 week after initiation of TVR and adjusted the dose of cyclosporine. The dose of cyclosporine was decreased 0.24-0.40 fold in all patients after initiation of TVR treatment. In 3 patients, the dose of TVR was decreased two-thirds of starting dose because of adverse effects, including anorexia and skin rash. However, the HCV RNA level rapidly decreased to undetectable levels within 1 month. Furthermore, all patients completed the TVR therapy in 12 weeks and did not experience liver graft rejection. In addition, we found the rapid elimination of inhibitory effect of TVR on the disposition of cyclospirne in the all four cases and therefore, rapid increase in the dosage of cyclosporine would be required immediately after the end of TVR administration. These results suggest that frequent measurement of cyclosporine levels was important for successful TVR triple therapy and prevention of rejection..
19. Eriko Sato, Sachiyo Hashi, Risa Taniguchi, Ikuko Yano, Kazuo Matsubara, Eri Ogawa, Atsushi Yoshizawa, Shinya Okamoto, Shinji Uemoto, Satohiro Masuda, Effectiveness of everolimus in combination with cyclosporine as treatment for chronic rejection in a pediatric patient undergoing liver transplantation, Jp J Ther Drug Monitor, 31, 1, 1-5, 2014.02, Everolimus has been approved as an immunosuppressant for heart and kidney transplantation in Japan, but its clinical use in infants has been very limited. We report the effective introduction of everolimus in combination with cyclosporine as treatment for chronic rejection in an 8-month-old girl who underwent living-donor liver transplantation (LDLT) for fulminant hepatitis. Oral tacrolimus was administered (0.5 mg every 12 h) from postoperative day (POD) 1, with the dose adjustments based on trough concentrations. On POD 60, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (T-Bil) were 120 U/L, 145 U/L, and 10.8 mg/dL, respectively, and chronic rejection was diagnosed by using pathologic examination. High-dose steroid pulse therapy decreased the AST and ALT levels, but the T-Bil level did not decrease until 11 days after the start of pulse therapy. We then substituted tacrolimus with a combination of cyclosporine (25 mg every 12 h) and everolimus (0.5 mg every 12 h). The dosages were adjusted based on the target trough concentrations of everolimus and cyclosporine (approximately 12-13 ng/mL and 180 ng/mL, respectively). Pharmacokinetic analysis showed the clearance for everolimus to be 0.147 L/hr/kg and the volume of distribution to be 12.6 L/kg. Thereafter, the serum level of T-Bil decreased to 3.0 mg/dL and pathologic examination showed amelioration of the chronic rejection. These results suggest that everolimus therapy in combination with cyclosporine is an effective treatment option for chronic rejection after liver transplantation..
20. Keiko Hosohata, Miwa Uesugi, Sachiyo Hashi, Mio Hosokawa, Ken-ichi Inui, Kazuo Matsubara, Kohei Ogawa, Yasuhiro Fujimoto, Toshimi Kaido, Shinji Uemoto, Satohiro Masuda, Association between CYP3A5 Genotypes in Graft Liver and Increase in Tacrolimus Biotransformation from Steroid Treatment in Living-donor Liver Transplant Patients, DRUG METABOLISM AND PHARMACOKINETICS, 10.2133/dmpk.DMPK-13-RG-060, 29, 1, 83-89, 2014.02, We retrospectively examined whether cytochrome P450 (CYP) 3A5 genotypes are associated with high-dose steroid pulse treatment-induced functional gain of tacrolimus biotransformation in living-donor liver transplant patients. Concentrations of tacrolimus and its 3 primary metabolites, 13-O-demethyl tacrolimus (M-I), 31-O-demethyl tacrolimus (M-II), and 15-O-demethyl tacrolimus (M-III), were measured in trough blood samples from 18 liver transplant patients, by liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS). In patients engrafted with a CYP3A5*1-carrying liver but not with a CYP3A5*3/*3-carrying liver, the concentration/dose ratio of tacrolimus significantly reduced after therapy, while ratios of M-I/tacrolimus, M-II/tacrolimus, and M-III/tacrolimus were significantly higher after therapy than before (p = 0.032, p = 0.023, and p = 0.0078, respectively). After steroid pulse therapy, the concentration of tacrolimus measured by immunoassay was significantly higher than that measured by LC-MS/MS in patients engrafted with a CYP3A5*1-carrying liver, but not those engrafted with a CYP3A5*3/*3-carrying liver. This suggests that the increased ratio of tacrolimus metabolites/tacrolimus can be explained by induction of CYP3A5 via high-dose steroid pulse therapy. Further, the concentrations of tacrolimus measured by the immunoassays were overestimated, partly because of cross-reactivity of the monoclonal antibody they incorporated to detect tacrolimus, with the increased metabolites in patients with a CYP3A5*1-carrying graft liver..
21. Miwa Uesugi, Mio Hosokawa, Haruka Shinke, Emina Hashimoto, Tamotsu Takahashi, Tomoki Kawai, Kazuo Matsubara, Kohei Ogawa, Yasuhiro Fujimoto, Shinya Okamoto, Toshimi Kaido, Shinji Uemoto, Satohiro Masuda, Influence of Cytochrome P450 (CYP) 3A4*1G Polymorphism on the Pharmacokinetics of Tacrolimus, Probability of Acute Cellular Rejection, and mRNA Expression Level of CYP3A5 Rather than CYP3A4 in Living-Donor Liver Transplant Patients, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 36, 11, 1814-1821, 2013.11, Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n=412) and/or recipients (n=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p=0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p=0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation..
22. Haruka Shinke, Sachiyo Hashi, Risa Kinoshita, Risa Taniguchi, Mitsuhiro Sugimoto, Kazuo Matsubara, Eri Ogawa, Mari Sonoda, Narito Takada, Atsushi Yoshizawa, Kohei Ogawa, Shinya Okamoto, Shinji Uemoto, Satohiro Masuda, Effectiveness of Sirolimus in Combination with Cyclosporine against Chronic Rejection in a Pediatric Liver Transplant Patient, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 36, 7, 1221-1225, 2013.07, The patient is a 3-year-old boy who received living-donor liver transplantation (LDLT) for hepatoblastoma, with his mother as the donor. Oral tacrolimus was started at a dose of 0.3 mg every 12 h from day 1, with the dosage adjusted on the basis of trough concentrations. The levels of aspartate aminotransferase (AST), alanine transferase (ALT), and total bilirubin (T-bil) were 110 U/L, 182 U/L, and 12.6 mg/dL, respectively, when chronic rejection (CR) was pathologically diagnosed. Then, sirolimus at a dose of 1.0 mg/day was added to the tacrolimus-based regimen. The T-bil level rapidly decreased to 5.4 mg/dL, without changes in AST and ALT. Because the intracellular receptor of sirolimus and tacrolimus is FK506-binding protein 12, we switched tacrolimus to cyclosporine at a dose of 60 mg/day to avoid competitive inhibition between these 2 drugs. The target trough concentration of sirolimus and cyclosporine was set to around 15 ng/mL and 180 ng/mL, respectively. The concentration/dose ratio of sirolimus was significantly correlated with the blood cyclosporine level (r = 0.5293, p < 0.05), suggesting the pharmacokinetic interaction between these 2 drugs. Thereafter, the levels of AST and ALT as well as the T-bil were successfully decreased to 73 U/L, 83 U/L, and 3.0 mg/dL, respectively. These results suggest that sirolimus therapy in combination with cyclosporine may be an effective treatment against CR after liver transplantation..
23. Kumiko Nishihara, Satohiro Masuda, Haruka Shinke, Aiko Ozawa, Takaharu Ichimura, Atsushi Yonezawa, Shunsaku Nakagawa, Ken-ichi Inui, Joseph V Bonventre, Kazuo Matsubara, Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity, BIOCHEMICAL PHARMACOLOGY, 10.1016/j.bcp.2012.12.019, 85, 4, 570-582, 2013.02, Because of the difficulty in detecting segment-specific response in the kidney, we investigated the molecular events underlying acute kidney injury in the proximal tubules of rats with cisplatin (cis-diamminedichloroplatinum II)-induced nephrotoxicity. Microarray analysis revealed that mRNA levels of several cytokines and chemokines, such as interleukin-1beta, chemokine (C-C motif) ligand (CCL) 2, CCL20, chemokine (C-X-C motif) ligand (CXCL) 1, and CXCL10 were significantly increased after cisplatin treatment in both isolated proximal tubules and whole kidney. Interestingly, tubular CCL2 mRNA levels increased soon after cisplatin administration, whereas CCL2 mRNA levels in whole kidney first decreased and then increased. Levels of both CCL2 and kidney injury molecule-1 (KIM-1) in the whole kidney increased after cisplatin administration. Immunofluorescence analysis revealed CCL2 changes in the proximal tubular cells initially and then in the medullary interstitium. Urinary CCL2 excretion significantly increased approximately 3-fold compared with controls the day after cisplatin administration (5mg/kg), when no changes were observed plasma creatinine and blood urea nitrogen levels. Urinary levels of KIM-1 also increased 3-fold after cisplatin administration. In addition, urinary CCL2 rather than KIM-1 increased in chronic renal failure rats after administration of low-dose cisplatin (2mg/kg), suggesting that urinary CCL2 was selective for cisplatin-induced nephrotoxicity in renal impairment. These results indicated that the increase in cytokine and chemokine expression in renal epithelial cells might be responsible for kidney deterioration in cisplatin-induced nephrotoxicity, and that urinary CCL2 is associated with tubular injury and serves as a sensitive and noninvasive marker for the early detection of cisplatin-induced tubular injury..
Presentations
1. Satohiro Masuda, Urinary biomarker for drug-induced nephrotoxicity, Predictive Safety Testing Consortium (PSTC) Japan Safety Biomarker Conference, 2017.02.
2. Hiroyuki Watanabe, Toshihiro Irisa, Koujiro Hata, Kazue Nakashima, Satohiro Masuda, Evaluation of the preparation precision of anticancer drugs by the Cancer Drug Compounding Assist System, FIP World Congress, 2016.09.
3. Hiroaki Ikesue, Hiroyuki Watanabe, Satohiro Masuda, Role of pharmacists in the safe and efficient care of patients receiving cancer treatment, FIP World Congress, 2016.09.
4. Satohiro Masuda, The standardization guideline and quality control surveillance in TDM of immunosuppressants in Japan, 2016 IATDMCT Regional Meeting, 2016.08.
5. Kojiro Hata, Hiroaki Ikesue, Shunichi Ohata, Hiroyuki Watanabe, Satohiro Masuda, Association between zoledronic acid-related kidney injury and concomitant administration of hydrophilic rather than lipophilic statins in cancer patients, 2015 Midyear Clinical Meeting and Exhibition, 50th ASHP, 2015.12.
6. M. Kajiwara, Y. Tamura, H. Shinke, S. Nakagawa, T. Yano, K. Matsubara, Satohiro Masuda, Gene expression analysis of isolated proximal tubules in rat model of tacrolimus-induced chronic kidney disease, Urine Omics & 2nd International Caparica Conference In Translational, 2015.09.
7. Satohiro Masuda, M. Kajiwara, A Tsuchimoto, H. Shinke, M. Uesugi, K. Matsubara, Identification of a useful biomarker for tacrolimus-induced nephrotoxicity in liver transplant patients, Urine Omics & 2nd International Caparica Conference In Translational, 2015.09.
8. Moto Kajiwara, Satohiro Masuda, Critical role of renal H+/organic cation antiporter (multidrug and toxin extrusion) in natriuresis as a dopamine transporter, BioMedical Transporters Conference 2015, 2015.08.
9. Satohiro Masuda, Role of OCT2/MATEs interplay in drug-induced nephrontoxicity, BioMedical Transporters Conference 2015, 2015.08.
10. Moto Kajiwara, Tsuyoshi Ban, Yuki Hanada, Kazuo Matsubara, Satohiro Masuda, Multidrug and toxin extrusion transporters play a key role in natriuresis as a dopamine transporter, EXPERIMENTAL BIOLOGY 2015, 2015.03.
11. Takahisa Yano • Yuya Sakamoto • Yuki Hanada • Aki Takeshita • Fumika Inagaki • Nobuaki Egashira • Satohiro Masuda, Vancomycin induced renal tubular cell injury by reactive oxygen species generation and mitochondrial dysfunction, EXPERIMENTAL BIOLOGY 2015, 2015.03.
12. Haruka Shinke, Yuka Tamura, Shunsuke Fujita, Shunsaku Nakagawa, Takahisa Yano, Kazuo Matsubara, Satohiro Masuda, Gene expression analysis of tacrolimus-induced tubulointerstitial fibrosis after ischemia/reperfusion injury, ASN Kidney Week 2013 Annual Meeting, 2014.11.
13. IATDMCT ISD committee, Concensus meeting in everolimus TMD methodology, IATDMCT ISD meeting, 2014.09.
Membership in Academic Society
  • Pharmaceutical Society of Japan, PSJ
  • Japanese Society for the Study of Xenobiotics, JSSX
  • Japanese Society of Pharmaceutical Health Care and Science, JSPHCS
  • Academy of Pharmaceutical Science and Technology, Japan, APSTJ
  • The Japanese Society of Therapeutic Drug Monitoring, JSTDM
  • Japanese Society of Clinical Pharmacology and Therapeutics, JSCPT
  • Japanese Society of Nephrology, JSN
  • The Japan Society for Transplantation, JST
  • The Japanese Association for Infectious Disease, JAID
  • The Japanese Society of Medical Oncology, JSMO
  • Japanese Society of Hospital Pharmacists, JSHP
  • American Society for Clinical Pharmacology and Therapeutics, ASCPT
  • American Society of Nephrology, ASN
  • International Society of Nephrology, ISN
  • American Physiological Society, APS
  • American Association of Pharmaceutical Scientists, AAPS
  • International Association of Therapeutic Drug Monitoring and Clinical Toxicology, IATDMCT
  • American Association of the Study for Liver Disease, AASLD
  • American Society of Health-System Pharmacists, ASHP
Awards
  • research in clinical application of genetic polymorphism and mRNA expression levels for personalized immunosuppressive therapy in liver transplant patients
  • Evaluation of intestinal expression level of P-glycoprotein as a risk factor of acute cellular rejection in recipients of living-donor liver transplantation
  • research in clarification and clinical application of pharmacokinetic factors in posttransplant immunosuppressive therapy
  • research in cDNA cloning, functional characteristics and pharmacokinetic significance of kidney-specific organic anion transporters
  • localization of kidney-specific organic anion transporter OAT-K1 and OAT-K2 along nephron and their drug recognition