Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug-drug interactions

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• 作者：H.J. Burt^a ; ^{Howard.burt@certara.com" class="auth_mail" title="E-mail the corresponding author} ; S. Neuhoff^a ; ^{Sibylle.neuhoff@certara.com" class="auth_mail" title="E-mail the corresponding author} ; L. Almond^a ; ^{Lisa.almond@certara.com" class="auth_mail" title="E-mail the corresponding author} ; L. Gaohua^a ; ^{Gaohua.lu@certara.com" class="auth_mail" title="E-mail the corresponding author} ; M.D. Harwood^a ; ^{Matthew.harwood@certara.com" class="auth_mail" title="E-mail the corresponding author} ; M. Jamei^a ; ^{Masoud.Jamei@certara.com" class="auth_mail" title="E-mail the corresponding author} ; A. Rostami-Hodjegan^a ; ^b ; ^{Amin.rostami@manchester.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; G.T. Tucker^c ; ^{G.t.tucker@sheffield.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; K. Rowland-Yeo^a ; ^{Karen.yeo@certara.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AUC ; area under the plasma concentration-time curve ; B/P ; blood-to-plasma ratio ; CYP ; cytochrome P450 ; CLint ; intrinsic clearance ; Cmax ; maximum plasma concentration ; CLPD ; passive permeability-surface area product ; DDI ; drug&ndash ; drug interaction ; fa ; fraction absorbed ; Jmax ; maximum rate of active transport ; JOCT1 ; rate of OCT1 transport ; JOCT2 ; rate of OCT2 transport ; ka ; absorption rate constant ; Ki ; inhibition constant ; Km ; Michaelis constant ; Kp ; tissue to plasma partition coefficient ; MA
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：10 June 2016
• 年：2016
• 卷：88
• 期：Complete
• 页码：70-82
• 全文大小：1345 K

文摘

Metformin is used as a probe for OCT2 mediated transport when investigating possible DDIs with new chemical entities. The aim of the current study was to investigate the ability of physiologically-based pharmacokinetic (PBPK) models to simulate the effects of OCT and MATE inhibition by cimetidine on metformin kinetics. PBPK models were developed, incorporating mechanistic kidney and liver sub-models for metformin (OCT and MATE substrate) and a mechanistic kidney sub-model for cimetidine. The models were used to simulate inhibition of the MATE1, MATE2-K, OCT1 and OCT2 mediated transport of metformin by cimetidine. Assuming competitive inhibition and using cimetidine K_i values determined in vitro, the predicted metformin AUC ratio was 1.0 compared to an observed value of 1.46. The observed AUC ratio could only be recovered with this model when the cimetidine K_i for OCT2 was decreased 1000-fold or the K_i's for both OCT1 and OCT2 were decreased 500-fold. An alternative description of metformin renal transport by OCT1 and OCT2, incorporating electrochemical modulation of the rate of metformin uptake together with 8–18-fold decreases in cimetidine K_i's for OCTs and MATEs, allowed recovery of the extent of the observed effect of cimetidine on metformin AUC. While the final PBPK model has limitations, it demonstrates the benefit of allowing for the complexities of passive permeability combined with active cellular uptake modulated by an electrochemical gradient and active efflux.