title: 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.
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK. Electronic address: Howard.burt@certara.com.
authors.forename: H J
authors.initials: HJ
authors.lastname: Burt
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK. Electronic address: Sibylle.neuhoff@certara.com.
authors.forename: S
authors.initials: S
authors.lastname: Neuhoff
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK. Electronic address: Lisa.almond@certara.com.
authors.forename: L
authors.initials: L
authors.lastname: Almond
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK. Electronic address: Gaohua.lu@certara.com.
authors.forename: L
authors.initials: L
authors.lastname: Gaohua
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK. Electronic address: Matthew.harwood@certara.com.
authors.forename: M D
authors.initials: MD
authors.lastname: Harwood
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK. Electronic address: Masoud.Jamei@certara.com.
authors.forename: M
authors.initials: M
authors.lastname: Jamei
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK; Manchester Pharmacy School, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. Electronic address: Amin.rostami@manchester.ac.uk.
authors.forename: A
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: Medicine and Biomedical Sciences (emeritus), University of Sheffield, Sheffield, UK. Electronic address: G.t.tucker@sheffield.ac.uk.
authors.forename: G T
authors.initials: GT
authors.lastname: Tucker
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK. Electronic address: Karen.yeo@certara.com.
authors.forename: K
authors.initials: K
authors.lastname: Rowland-Yeo
mesh_terms: D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics*; D002927:Cimetidine / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004337:Drug Carriers; D004347:Drug Interactions; D004563:Electrochemistry; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008687:Metformin / Q000493:pharmacokinetics*; D008954:Models, Biological; D027701:Organic Cation Transport Proteins / Q000378:metabolism
chemical_list: D000897:Anti-Ulcer Agents; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D002927:Cimetidine; D008687:Metformin
keywords: Drug transporters; Drug–drug interactions; IVIVE; PBPK