Influence of nicardipine and nifedipine on plasma carvedilol disposition after oral administration in rats

Abstract

The effect of two kinds of 1,4-dihydropyridine calcium-channel blockers, nicardipine hydrochloride and nifedipine, on the disposition of carvedilol, was studied in rats. Blood samples were assayed for carvedilol levels using solid-phase extraction and high-performance liquid chromatography. The plasma carvedilol concentration was found to be significantly higher, and the area under the concentration-time curve up to 24 h (AUC0-->24) was 6.7 and 3.0 times higher after simultaneous oral administration of 20 mg kg(-1) carvedilol with 40 mg kg(-1) nicardipine hydrochloride, or with 40 mg kg(-1) nifedipine, respectively, than after administration of carvedilol alone. The pharmacokinetic interaction between carvedilol and dihydropyridine calcium-channel blockers is thought to be attributable to vasodilator-induced changes in hepatic first-pass metabolism, inhibition in the absorption barrier by P-glycoprotein and in the metabolism of carvedilol.

Nifedipine Does Not Alter the Pharmacokinetics of Venlafaxine Enantiomers in Healthy Subjects Phenotyped for CYP2D6, CYP2C19, and CYP3A

“…All the investigated healthy subjects were previously pheno-typed as EMs for CYP2D6, CYP2C19, and CYP3A using VEN, metoprolol, and omeprazole as probe drugs (Table 1 and Supplementary Files). Because nifedipine had a role in P-gp inhibition in some in vitro and experimental studies, [20][21][22][23] we hypothesized that a single oral dose of 40 mg, a high dose considered safe in clinical studies, could inhibit the intestinal P-gp and consequently increases VEN bioavailability.…”

“…Although many substrates of P‐gp are also substrates of CYP3A, nifedipine, a calcium channel blocker inhibitor used in the clinical treatment of hypertension, is reported as a substrate of CYP3A but not of P‐gp 19 . However, nifedipine is reported by some authors as a P‐gp inhibitor in in vitro and experimental studies 20–23 . It has been reported that 50 μM nifedipine inhibited the net transport and increased the intracellular accumulation of 3.6 nM [ 3 H] digoxin in Caco‐2 cells 20 and 10‐100 μM nifedipine inhibited the transport of 5 μM [ 3 H]‐digoxin in Caco‐2 cells by 36% to 56% 21 .…”

“…It has been reported that 50 μM nifedipine inhibited the net transport and increased the intracellular accumulation of 3.6 nM [ 3 H] digoxin in Caco‐2 cells 20 and 10‐100 μM nifedipine inhibited the transport of 5 μM [ 3 H]‐digoxin in Caco‐2 cells by 36% to 56% 21 . Different doses of nifedipine administered to rats also prove to inhibit P‐gp 22,23 . A single oral dose of nifedipine (40 mg/kg) increased by 3 times the area under the plasma concentration‐versus‐time curve (AUC) of carvedilol, 22 a substrate and an inhibitor of P‐gp 24–26 in rats, probably because nifedipine inhibited P‐gp with a consequent increase in carvedilol bioavailability.…”

“…21 Different doses of nifedipine administered to rats also prove to inhibit P-gp. 22,23 A single oral dose of nifedipine (40 mg/kg) increased by 3 times the area under the plasma concentration-versus-time curve (AUC) of carvedilol, 22 a substrate and an inhibitor of P-gp [24][25][26] in rats, probably because nifedipine inhibited P-gp with a consequent increase in carvedilol bioavailability. In addition, a single oral dose of nifedipine (3 mg/kg, but not 1 mg/kg) modified AUC, apparent total clearance (CL/F), and bioavailability (F) of repaglinide 23 because of the inhibition of the CYP3A4 metabolism and P-gp transport in the small intestine and/or hepatic metabolism.…”

High-Performance Liquid Chromatography Determination of Carvedilol in Pig Serum

“…Several chromatographic methods have been developed for the determination of carvedilol in biological samples, plasma (4)(5)(6)(7)(8)(9), serum (10,11), urine (12,13), and cardiac tissue (14). Most of these methods are focused on the separation of enantiomers (7)(8)(9).…”