Effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats

Abstract

The present study aimed to investigate the effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats. The pharmacokinetic parameters of verapamil were measured after an oral (9 mg/kg) or intravenous (3 mg/kg) administration of verapamil to rats in the presence and absence of atorvastatin. Compared with the control given verapamil alone, the concurrent use of 1.5 mg/kg of atorvastatin significantly increased the oral exposure of verapamil in rats. The AUC and C(max) of verapamil increased by 70% and 61%, respectively in the presence of atorvastatin (1.5 mg/kg), while there was no significant change in T(max) and the terminal plasma half-life (T(1/2)) of verapamil. Accordingly, the presence of atorvastatin significantly (p<0.05) increased the bioavailability of verapamil in rats. In contrast, atorvastatin had no effect on any pharmacokinetic parameters of verapamil given intravenously, implying that atorvastatin may improve the oral bioavailability of verapamil by reducing the prehepatic extraction of verapamil most likely mediated by P-gp and/or CYP3A4. In conclusion, coadministration of atorvastatin significantly enhanced the oral exposure of verapamil in rats without a change in the systemic clearance of intravenous verapamil, suggesting a potential drug interaction between verapamil and atorvastatin via the modulation of prehepatic extraction.

Effects of Atorvastatin on the Pharmacokinetics of Nicardipine after Oral and Intravenous Administration in Rats

“…nicardipine, suggesting that atorvastatin did not inhibit the metabolism of nicardipine via hepatic CYP3A subfamily and renal excetion in rats. This result appeared to be consistent with a previous report that oral administration of atrovasatatin significantly increased the oral bioavailability of verapamil in rats (Choi et al, 2008).…”

“…Calcium-channel blockers increased plasma concentrations of some statins (lovastatin, pravastatin and simvastatin), possibly through the inhibition of CYP 3A4 and P-gp (Azie et al, 1998;Mousa et al, 2000). But there are fewer reports about the effects of HMG-CoA reductase inhibitors on the bioavailability or pharmacokinetics of calcium channel antagonists in rats (Choi et al, 2006;Choi et al, 2008). Moreover, atorvastatin and nicardipine could be prescribed for the prevention or treatment of cardiovascular diseases as a combination therapy.…”

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors

“…There are some papers that the results obtained in vivo in rats could be extrapolate on humen from results obtained in vitro with human CYP3A4 and P-gp. As CYP3A9 expressed in rat corresponds to the ortholog of CYP3A4 in human [27,42,43], and rat CYP3A2 is similar to human CYP3A4 [29,30,44]. Human CYP2C9 and 3A4 and rat CYP2C11 and 3A4 are 77% and 73% homologous, respectively [31,32,45].…”

“…Calcium-channel blockers increase the plasma concentrations of some statins, possibly through the inhibition of CYP 3A4 and P-gp [27,28]. However, few studies have reported about the effects of HMG-CoA reductase inhibitors on the bioavailability or pharmacokinetics of antihypertensive agents [29][30][31][32]. Although a combination of nifedipine and statins have been clinically prescribed for treatment of hypertension, the pharmacokinetic interaction between a HMG-CoA reductase inhibitor and nifedipine in vivo has not been reported thus far.…”

Effects of Amlodipine on the Pharmacokinetics of Warfarin after Oral and Intravenous Administration of Warfarin in Rats

“…2). As amlodipine is an inhibitor of CYP3A4, con- www.biomolther.org comitant use of the drug might play a role in the wide inter-individual variability in the response to drugs (Choi et al, 2006;Choi et al, 2008). Most calcium channel blockers (verapamil, nifedipine, diltiazem, barnidipine) also have inhibitory effect on the drug transporter P-gp, which mediates drug's intestinal absorption (Yusa and Tsuruo, 1989;Wacher et al, 2001).…”