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

Abstract

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 Ki 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 Ki for OCT2 was decreased 1000-fold or the Ki'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 Ki'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.

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

“…This contrasts with published models of rat kidney, for which the available data support the mathematical description of features such as exponential decline in proximal tubule filtrate flow and compliant tubules (61). Despite uncertainties associated with some human kidney systems parameters, recent modelling efforts have attempted to account for the impact of flow rates and pH on tubular drug reabsorption (29), as well as the effects electrochemical gradients on organic cation transporter (OCT) 2 (OCT2, SLC22A2)-mediated secretion (59) in mechanistic kidney models. The importance of accounting for the impact of urine pH on proton gradient-dependent drug transport by MATE1 and MATE2-K, as described in vitro (103), should also be assessed.…”

“…Compartmental modelling approaches are recommended for estimation of mechanistic efflux transporter kinetic parameters in monolayer assays (53,55,56). These models differ in their complexity and may also consider membrane partitioning and organelle (lysosomes) sequestration, ionised drug permeation, impact of the unstirred water layer and the contribution of electrochemical gradients (53,(56)(57)(58)(59). The key advantage of these models is consideration of the interaction of an efflux transporter with the unbound intracellular drug concentration, as opposed to nominal incubation concentration.…”

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

“…Further refinement of mechanistic modelling of transporter kinetics may result in a more mechanistic input in PBPK kidney models, as illustrated with consideration of electrochemical gradient on organic cation (OCT) mediated uptake of metformin (19). Other features of transporter kinetics that may be considered in the future include role of ATP concentrations, impact of concentration gradients (pH, sodium or other ions) and differences between antiporters and symporters.…”

“…Both active secretion and reabsorption can be described using well-stirred or parallel tube models, relating the intrinsic secretion clearance to the renal blood flow (secretion), or the tubular filtrate flow (reabsorption) (11,22). Few studies have compared different structures or refined versions of mechanistic kidney models in specific scenarios (19,37), and further studies of this nature are recommended.…”

“…abundances in human kidney and in vitro systems) are lacking, and therefore the proposed IVIVE approach is not currently feasible (1). Instead, empirical optimisation of transporter activities or REF/RAF parameters using clinical data has been applied to adequately describe clinically observed CL R (18,19,39) (Table I). In some instances, as illustrated in the case of veliparib, REF scaling was not necessary for successful IVIVE of CL R (40).…”