Pharmacokinetics of the Enantiomers of Verapamil After Intravenous and Oral Administration of Racemic Verapamil in a Rat Model

Abstract

Verapamil is a chiral calcium channel blocking drug which is useful clinically as the racemate in treating hypertension and arrhythmia. The published pharmacokinetic data for verapamil enantiomers in the rat model are limited. Utilizing a stereospecific high‐performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of verapamil is reported after intravenous (1·0 mg kg−1) and oral (10 mg kg−1) administration of racemic verapamil to the rat model. After intravenous administration the systemic clearance of R‐verapamil was significantly greater than that of S‐verapamil; 34·9 ± 7 against 2·7 ± 3·7 mL min−1 kg−1 (mean ± SD), respectively. After oral administration, the clearance of R‐verapamil was significantly greater than that of S‐verapamil, 889 ± 294 against 351 ± 109 mL min−1 kg−1, respectively. The apparent oral bioavailability of S‐verapamil was greater than that of R‐verapamil, 0·074 ± 0·031 against 0·041 ± 0·011, respectively. These data suggest that the disposition of verapamil in the rat is stereoselective; verapamil undergoes extensive stereoselective first‐pass clearance after oral administration and the direction of stereoselectivity in plasma is opposite to that observed in the human. © 1997 John Wiley & Sons, Ltd.

Differentiation of Gut and Hepatic First-Pass Loss of Verapamil in Intestinal and Vascular Access-Ported (Ivap) Rabbits

“…Since VL is a substrate for CYP3A4 and, potentially, its isoform CYP3A6 in rabbit and P-gp (Saitoh and Aungst, 1995;Fromm et al, 1996), high intestinal secretion and metabolism were anticipated in vivo. Previously, VL was shown to be completely absorbed from the gastrointestinal tract (Echizen and Eichelbaum, 1986), and yet it exhibits low and varied oral bioavailability (BA), ranging from 7 to 30% in rats, dogs, and humans (Echizen and Eichelbaum, 1986;Bhatti and Foster, 1997;Lee et al, 2001). In this report, the relative contribution of the gut and liver toward the first-pass extraction of VL was assessed in IVAP rabbits.…”

Pharmacokinetics of Intravenous and Oral Metformin and R,S-Verapamil in Sinclair, Hanford, Yucatan and Göttingen Minipigs

“…In humans, MET is not metabolized and is cleared from the body by renal tubular secretion and excreted unchanged in the urine; MET is undetectable in blood plasma within 24 h of a single oral dose with a mean plasma elimination half-life after oral administration of between 4.0 and 8.7 h [17]. R,S-verapamil (R,S-VER), a calcium channel-blocker, is a chiral drug that is administered as a racemic mixture and is known to undergo an extensive enantioselective first-pass effect after oral administration [18]. R,S-VER undergoes extensive oxidative metabolism with formation of an active metabolite norverapamil (NOR) [19].…”

Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence

“…However, doses of 20, 40 and 80 mg·kg −1 ·day −1 were suggested to be inappropriately high doses for the following reasons. The maximum plasma concentration after oral administration of verapamil at doses of 80–120 mg·day −1 in humans is lower than or at least equal to that after oral administration of 10 mg·kg −1 verapamil in rats (Echizen and Eichelbaum, 1986; Bhatti and Foster, 1997). Moreover, 2 mg·kg −1 of verapamil significantly decreased both arterial pressure and cardiac output in rats (Lay et al ., 2006).…”