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Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2.

ABSTRACT: BACKGROUND AND PURPOSE: Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats. EXPERIMENTAL APPROACH: Itraconazole (20 mg·kg(-1)) and metformin (100 mg·kg(-1)) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V(max)), Michaelis-Menten constant (K(m)) and intrinsic clearance (CL(int) ) for the disappearance of each drug, apparent inhibition constant (K(i) ) and [I]/K(i) ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro. KEY RESULTS: After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration-time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes. CONCLUSIONS AND IMPLICATIONS: The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2.

SUBMITTER: Choi YH

PROVIDER: S-EPMC2992897 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

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Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2.

Choi Y H YH Lee U U Lee B K BK Lee M G MG

British journal of pharmacology 20101001 4

<h4>Background and purpose</h4>Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats.<h4>Experimental approach</h4>Itraconazole (20 mg·kg(-1)) and metformin (100 mg·kg(-1)) were simultaneously administered i.v. an ...[more]

PMID: 20860661

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Project description:An aspalathin-rich green rooibos extract (Afriplex GRT™) has demonstrated anti-diabetic and hypolipidemic properties, while also moderately inhibiting CYP3A4 activity, suggesting a potential for herb-drug interaction. The present study, therefore, evaluated the effects of orally administered GRT on the pharmacokinetics of atorvastatin and metformin in Wistar rats. Wistar rats were orally treated with GRT (50 mg/kg BW), atorvastatin (40 mg/kg BW) or metformin (150 mg/kg BW) alone or 50 mg/kg BW GRT in combination with 40 mg/kg BW atorvastatin or 150 mg/kg BW metformin. Blood samples were collected at 0, 10, and 30 min and 1, 2, 4, 6, and 8 h and plasma samples obtained for Liquid chromatography-mass spectrometry (LC-MS/MS) analyses. Non-compartment and two-compartment pharmacokinetic parameters of atorvastatin and metformin in the presence or absence of GRT were determined by PKSolver version 2.0 software. Membrane transporter proteins, ATP-binding cassette sub-family C member 2 (Abcc2), solute carrier organic anion transporter family, member 1b2 (Slco1b2), ATP-binding cassette, sub-family B (MDR/TAP), member 1A (Abcb1a), and organic cation transporter 1 (Oct1) mRNA expression were determined using real-time PCR expression data normalized to ?-actin and hypoxanthine-guanine phosphoribosyltransferase (HPRT), respectively. Co-administration of GRT with atorvastatin substantially increased the maximum plasma concentration (Cmax) and area of the plasma concentration-time curve (AUC0-8) of atorvastatin by 5.8-fold (p = 0.03) and 5.9-fold (p = 0.02), respectively. GRT had no effect on the plasma levels of metformin. GRT increased Abcc2 expression and metformin downregulated Abcb1a expression while the combination of GRT with atorvastatin or metformin did not significantly alter the expression of Slco1b1 or Oct1 did not significantly alter the expression of Sclo1b2 or Oct1. Co-administration of GRT with atorvastatin in rats may lead to higher plasma concentrations and, therefore, to an increase of the exposure to atorvastatin.

Project description:BACKGROUND:Metformin is a widely prescribed antidiabetic BCS Class III drug (low permeability) that depends on active transport for its absorption and disposition. It is recommended by the US Food and Drug Administration as a clinical substrate of organic cation transporter 2/multidrug and toxin extrusion protein for drug-drug interaction studies. Cimetidine is a potent organic cation transporter 2/multidrug and toxin extrusion protein inhibitor. OBJECTIVE:The objective of this study was to provide mechanistic whole-body physiologically based pharmacokinetic models of metformin and cimetidine, built and evaluated to describe the metformin-SLC22A2 808G>T drug-gene interaction, the cimetidine-metformin drug-drug interaction, and the impact of renal impairment on metformin exposure. METHODS:Physiologically based pharmacokinetic models were developed in PK-Sim® (version 8.0). Thirty-nine clinical studies (dosing range 0.001-2550 mg), providing metformin plasma and urine data, positron emission tomography measurements of tissue concentrations, studies in organic cation transporter 2 polymorphic volunteers, drug-drug interaction studies with cimetidine, and data from patients in different stages of chronic kidney disease, were used to develop the metformin model. Twenty-seven clinical studies (dosing range 100-800 mg), reporting cimetidine plasma and urine concentrations, were used for the cimetidine model development. RESULTS:The established physiologically based pharmacokinetic models adequately describe the available clinical data, including the investigated drug-gene interaction, drug-drug interaction, and drug-drug-gene interaction studies, as well as the metformin exposure during renal impairment. All modeled drug-drug interaction area under the curve and maximum concentration ratios are within 1.5-fold of the observed ratios. The clinical data of renally impaired patients shows the expected increase in metformin exposure with declining kidney function, but also indicates counter-regulatory mechanisms in severe renal disease; these mechanisms were implemented into the model based on findings in preclinical species. CONCLUSIONS:Whole-body physiologically based pharmacokinetic models of metformin and cimetidine were built and qualified for the prediction of metformin pharmacokinetics during drug-gene interaction, drug-drug interaction, and different stages of renal disease. The model files will be freely available in the Open Systems Pharmacology model repository. Current guidelines for metformin treatment of renally impaired patients should be reviewed to avoid overdosing in CKD3 and to allow metformin therapy of CKD4 patients.

Dataset Information

Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2.

Publications

Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2.

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