Research Paper
Subject Category: Pharmacokinetics, drug metabolism, toxicology
British Journal of Pharmacology (2008) 153, 1568–1578; doi:10.1038/sj.bjp.0707680; published online 21 January 2008
Pharmacokinetic interaction between DA-8159, a new erectogenic, and metformin in rats: competitive inhibition of metabolism via hepatic CYP3A1/2
Y H Choi1, S J Chung1 and M G Lee1
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
Correspondence: Professor MG Lee, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea. E-mail: leemg@snu.ac.kr
Received 13 July 2007; Revised 12 September 2007; Accepted 10 December 2007; Published online 21 January 2008.
Abstract
Background and purpose:
Erectile dysfunction is highly prevalent in diabetic patients and PDE V inhibitors are effective and safe for the treatment of erectile dysfunction in men with diabetes. Therefore, in this study we investigated whether a pharmacokinetic interaction occurs between DA-8159 and metformin, as both drugs are metabolized via hepatic CYP3A1/2 in rats.
Experimental approach:
DA-8159 (30 mg kg–1) and metformin (100 mg kg–1), both separately and together, were administered to rats either intravenously or orally. The V max, K m, CLint, apparent inhibition constants (K i), [I]/K i and concentrations of each drug in the liver and intestine were then measured.
Key results:
After i.v. administration of both drugs simultaneously, the AUC of DA-8159 and metformin was significantly greater (21.2 and 33.9% increase for DA-8159 and metformin, respectively) than that of each drug alone. After p.o. administration of the drugs, the AUC of metformin was also significantly greater (20.7% increase) in the presence of DA-8159 than in its absence. However, the AUC of DA-8159 was similar in the absence and presence of metformin.
Conclusions and implications:
The significantly greater AUC of metformin and DA-8159 after i.v. administration of both drugs and of metformin after p.o. administration of both drugs is probably due to competitive inhibition for the metabolism of these drugs via hepatic CYP3A1/2. However, the similar AUCs of DA-8159 in the absence and presence of metformin, after p.o. administration, indicates that the dose of metformin used was insufficient to inhibit the hepatic and intestinal metabolism of DA-8159.
Keywords:
pharmacokinetic interaction, DA-8159, metformin, competitive inhibition, hepatic CYP3A1/2
Abbreviations:
Ae0–24 h, percentage of the dose excreted in the 24-h urine; AUC, total area under the plasma concentration–time curve from time zero to time infinity; Cmax, peak plasma concentration; CL, time-averaged total body clearance; CLint, intrinsic clearance; CLNR, time-averaged nonrenal clearance; CLR, time-averaged renal clearance; F, extent of absolute oral bioavailability; GI24 h, percentage of the dose recovered from the entire gastrointestinal tract (including its contents and faeces) at 24 h; Ki, inhibition constant; Km, Michaelis–Menten constant; t1/2, half-life; Tmax, time to reach Cmax; Vmax, maximum velocity; Vss, apparent volume of distribution at steady state
