Amlodipine Inhibits Rat Microsomal Cytochrome P450-Mediated Drug Biotransformation

Abstract

Calcium channel antagonists have been shown to inhibit cytochrome P-450-mediated metabolism both in vitro and in vivo. The purpose of the present study was to examine the effect of amlodipine on a suite of rat hepatic microsomal cytochrome P-450 activities to determine the potential for drug interactions. In this study, amlodipine (0.05 and 0.5 mM) decreased CYP1A-mediated ethoxyresorufin O-deethylase activity in microsomes prepared from noninduced (56 and 73% inhibition) and pyridine-induced (30 and 51% inhibition) rats. Amlodipine reduced pentoxyresorufin O-deethylase activity (a marker for CYP2B) to 15% of control in incubations utilizing microsomes from phenobarbital-treated rats, but had no effect on this enzyme reaction in noninduced microsomes. The para-nitrophenol hydroxylase, erythromycin N-demethylase, and lauric acid omega and omega-1 hydroxylase activities were significantly inhibited by 1 mM amlodipine in both noninduced and induced microsomes. These results suggest that amlodipine inhibits a number of different P450 forms and therefore has the potential to inhibit the metabolism of a large number of drugs.

Negligible pharmacokinetic interaction between oral DA-8159, a new erectogenic, and amlodipine in rats

“…Amlodipine inhibited erythromycin N-demethylase activity in the rat liver microsomes [10], however, it appears unpublished whether CYP3A1/2 is involved in the metabolism of amlodipine in rats in vivo. Hence, rats were pretreated with troleandomycin, a main inhibitor of CYP3A1/2 in rats [16].…”

“…Drobitch et al [10] reported that erythromycin N-demethylase (erythromycin is metabolized to N-demethylerythromycin via CYP3A2 in male rats [11]) activity was significantly inhibited by 1 mm amlodipine in both noninduced and induced rat liver microsomes. However, whether CYP3A1/2 is involved in the metabolism of amlodipine in rats in vivo seemed not to be reported.…”

“…However, whether CYP3A1/2 is involved in the metabolism of amlodipine in rats in vivo seemed not to be reported. Since, metabolism of DA-8159 and the formation of DA-8164 were mainly mediated by CYP3A1/2 in rats [7] and amlodipine inhibited CYP3A2 in rats [10], the pharmacokinetic interaction between DA-8159 and amlodipine could be expected in rats. Pharmacokinetic and/or pharmacodynamic interactions between DA-8159 and other drugs in rats were reported.…”

Effect of amlodipine on the pharmacokinetics of tacrolimus in rats

“…Hence, AML is often used in hypertensive patients after transplantation. Erythromycin is metabolized to Ndemethylerythromycin via CYP3A2 in male rats (Desjardins & Iversen, 1995) and the N-demethylase activity of erythromycin has been shown to be significantly inhibited by 1 mM AML in non-induced and induced rat liver microsomes, suggesting that CYP3A2 activity is inhibited by AML in rats (Drobitch et al, 1997). Human CYP3A4 is similar to rat CYP3A2 (Bogaards et al, 2000).…”

“…AML is an inhibitor of CYP3A2 in rats (Drobitch et al, 1997) and a substrate of P-gp (Katoh et al, 2000;Kuzuya et al, 2003). Only one clinical case report (Leroy et al, 2010) has suggested that AML might increase the TAC concentration.…”