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Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3.
Biochem Pharmacol. 2007 Jun 30; 74(1):161-8.BP

Abstract

The immunosuppressant mycophenolate mofetil (MMF) is frequently administered with calcineurin inhibitors and corticosteroids to recipients of organ transplantations. However, the renal handling of the active metabolite mycophenolic acid (MPA) and 7-O-MPA-glucuronide (MPAG) has been unclear. The purpose of the present study was to assess the interaction of MPA and MPAG with the human renal organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8), by conducting uptake experiments using HEK293 cells stably expressing these transporters. MPA and MPAG inhibited the time-dependent uptake of p-[(14)C]aminohippurate by hOAT1 and that of [(3)H]estrone sulfate by hOAT3. The apparent 50% inhibitory concentration (IC(50)) of MPA for hOAT1 and hOAT3 was estimated at 10.7 and 1.5 microM, respectively. In the case of MPAG, the IC(50) values were calculated at 512.3 microM for hOAT1 and 69.1 microM for hOAT3. Eadie-Hofstee plot analyses showed that they inhibited hOAT1 noncompetitively and hOAT3 competitively. No inhibitory effects of tacrolimus, cyclosporin A and azathioprine on transport of p-[(14)C]aminohippurate by hOAT1 and of [(3)H]estrone sulfate by hOAT3 were observed. No transport of MPA by these transporters was observed. On the other hand, the uptake of MPAG into cells was stimulated by the expression of hOAT3, but not hOAT1. These findings propose the possibility that the administration of MMF decreases the renal clearance of drugs which are substrates of hOAT1 and hOAT3. Present data suggest that hOAT3 contributes to the renal tubular secretion of MPAG.

Authors+Show Affiliations

Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17462604

Citation

Uwai, Yuichi, et al. "Interaction and Transport Characteristics of Mycophenolic Acid and Its Glucuronide Via Human Organic Anion Transporters hOAT1 and HOAT3." Biochemical Pharmacology, vol. 74, no. 1, 2007, pp. 161-8.
Uwai Y, Motohashi H, Tsuji Y, et al. Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3. Biochem Pharmacol. 2007;74(1):161-8.
Uwai, Y., Motohashi, H., Tsuji, Y., Ueo, H., Katsura, T., & Inui, K. (2007). Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3. Biochemical Pharmacology, 74(1), 161-8.
Uwai Y, et al. Interaction and Transport Characteristics of Mycophenolic Acid and Its Glucuronide Via Human Organic Anion Transporters hOAT1 and HOAT3. Biochem Pharmacol. 2007 Jun 30;74(1):161-8. PubMed PMID: 17462604.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3. AU - Uwai,Yuichi, AU - Motohashi,Hideyuki, AU - Tsuji,Yoshie, AU - Ueo,Harumasa, AU - Katsura,Toshiya, AU - Inui,Ken-ichi, Y1 - 2007/03/30/ PY - 2006/12/28/received PY - 2007/03/21/revised PY - 2007/03/22/accepted PY - 2007/4/28/pubmed PY - 2007/7/20/medline PY - 2007/4/28/entrez SP - 161 EP - 8 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 74 IS - 1 N2 - The immunosuppressant mycophenolate mofetil (MMF) is frequently administered with calcineurin inhibitors and corticosteroids to recipients of organ transplantations. However, the renal handling of the active metabolite mycophenolic acid (MPA) and 7-O-MPA-glucuronide (MPAG) has been unclear. The purpose of the present study was to assess the interaction of MPA and MPAG with the human renal organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8), by conducting uptake experiments using HEK293 cells stably expressing these transporters. MPA and MPAG inhibited the time-dependent uptake of p-[(14)C]aminohippurate by hOAT1 and that of [(3)H]estrone sulfate by hOAT3. The apparent 50% inhibitory concentration (IC(50)) of MPA for hOAT1 and hOAT3 was estimated at 10.7 and 1.5 microM, respectively. In the case of MPAG, the IC(50) values were calculated at 512.3 microM for hOAT1 and 69.1 microM for hOAT3. Eadie-Hofstee plot analyses showed that they inhibited hOAT1 noncompetitively and hOAT3 competitively. No inhibitory effects of tacrolimus, cyclosporin A and azathioprine on transport of p-[(14)C]aminohippurate by hOAT1 and of [(3)H]estrone sulfate by hOAT3 were observed. No transport of MPA by these transporters was observed. On the other hand, the uptake of MPAG into cells was stimulated by the expression of hOAT3, but not hOAT1. These findings propose the possibility that the administration of MMF decreases the renal clearance of drugs which are substrates of hOAT1 and hOAT3. Present data suggest that hOAT3 contributes to the renal tubular secretion of MPAG. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/17462604/Interaction_and_transport_characteristics_of_mycophenolic_acid_and_its_glucuronide_via_human_organic_anion_transporters_hOAT1_and_hOAT3_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(07)00192-X DB - PRIME DP - Unbound Medicine ER -