Pharmacokinetic interaction between DA-8159, a new erectogenic, and metformin in rats: Competitive inhibition of metabolism via hepatic CYP3A1/2

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, CL _int, 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.