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

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

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...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences Vol. 88; pp. 70 - 82
Main Authors: Burt, H.J., Neuhoff, S., Almond, L., Gaohua, L., Harwood, M.D., Jamei, M., Rostami-Hodjegan, A., Tucker, G.T., Rowland-Yeo, K.
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 10-06-2016
Subjects:
Anti-Ulcer Agents - pharmacokinetics
Cimetidine - pharmacokinetics
Computer Simulation
Drug Carriers
Drug Interactions
Drug transporters
Drug–drug interactions
Electrochemistry
Hypoglycemic Agents - pharmacokinetics
IVIVE
Kidney - metabolism
Liver - metabolism
Metformin - pharmacokinetics
Models, Biological
Organic Cation Transport Proteins - metabolism
PBPK
OCT
CLPD
Km
B/P
OAT
Mech KiM
Kp
tmax
Φm
IVIVE
DDI
PBPK
PerL
JOCT2
JOCT1
AUC
Drug–drug interactions
PMAT
ka
CYP
Cmax
Φdf
MATE
tlag
Drug transporters
CLint
PE
RAF
Vss
Jmax
fa
Ki
PTC
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Summary: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. [Display omitted]
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ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2016.03.020