Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model |
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| Affiliation: | 1. Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan;2. Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda-shi, Saitama 335-8505, Japan;3. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;1. Drug Assay Device Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8565, Tokyo, Japan;2. Department of Chemical System Engineering, Graduate School of Engineering, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8656, Japan;3. International Research Center on Integrative Biomedical Systems (CIBiS), Institute of Industrial Science, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo, 153-8505, Japan;1. Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan;2. Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, 980-8574, Japan;3. Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan;4. Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8575, Japan;1. Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan;2. Department of Pharmacy, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyoku, Tokyo, 113-8655, Japan;1. Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan;2. DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, 335-8505, Japan |
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| Abstract: | Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CLcre), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters. |
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| Keywords: | Clinical pharmacokinetics Creatinine Drug interaction PBPK model Quantitative analysis Renal transporter Trimethoprim |
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