Pharmacokinetics of the enantiomers of verapamil in the dog

Abstract

The intravenous (0.5 mg/kg) and oral (5 mg/kg) dose kinetics of verapamil were studied in 6 dogs during steady-state oral verapamil dosing (5 mg/kg every 8 h for 3 days). Racemic verapamil and norverapamil, a metabolite of verapamil, were quantitated in plasma by HPLC-fluorescence detection. The verapamil peaks eluting off the column were collected and rechromatographed on an Ultron-OVM column, which resolved the two verapamil enantiomers. After intravenous administration, the systemic clearance and apparent volume of distribution of (-)-(S)-verapamil were nearly twice that of the (+)-(R)-isomer. There was no difference in the elimination half-lives between the two isomers. After oral administration, the oral clearance of (-)-(S)-verapamil was 20 times that of the (+)-(R)-isomer. The apparent bioavailability of (+)-(R)-verapamil was over 14 times that of (-)-(S)-verapamil. The plasma protein binding of the (+)-(R)-isomer was slightly higher by 5% than (-)-(S)-verapamil; however, this effect was not enough to account for the difference between the apparent volume of distribution of the enantiomers, indicating that the tissue binding of (-)-(S)-verapamil was greater than that of the (+)-(R)-isomer. This data on the disposition of the enantiomers of verapamil in the dog is similar to that reported for man and demonstrates that the dog may be an appropriate animal model for man in future studies on the disposition of the enantiomers of verapamil.

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

“…The pharmacokinetics of enantiomers of verapamil have also been studied in dogs and rabbits. 4,10 Bai et al 10 reported stereoselective disposition of verapamil in dogs and found that the Cl s , Cl o and V db values of S-verapamil were greater than those of R-verapamil and that the oral bioavailability of R-verapamil was 14 times greater than that of S-verapamil. These dierences between the bioavailabilities of the enantiomers in dogs were much greater than that found (fourfold) in man.…”

“…4,6±10 Although the kinetics of the individual enantiomers of verapamil in human have been extensively studied, a review of the literature reveals that there is a scarcity of stereospeci®c studies of verapamil in animals. 4,10 In view of the increasing interest in interspecies scaling up of absorption 11,12 and disposition kinetics 13±15 and of the ®ndings that the rat may serve as a good model for the human in p.o. absorption, 10 it was decided to study, in detail, the kinetics of verapamil enantiomers in male Sprague±Dawley rats.…”

Role of biological matrices during the analysis of chiral drugs by liquid chromatography

“…The extent of stereoselective plasma binding of drugs ranges up to a factor of about 1.5, reflecting a diastereomeric association with both albumin, the major binding protein for most acids (warfarin, ketoprofen [25], zopiclone [26]) and with AGP, which binds predominantly basic compounds (verapamil [27], propranolol [28]). Propranolol illustrates a case where the stereoselectivity of binding occurs in opposite directions for the different proteins.…”

Pharmacokinetics of Verapamil in New Zealand White Rabbits during Ontogeny

“…Moreover, its use for the treatment of hypertension during ontogeny has been postulated [5,6]. The pharmacokinetics of verapamil has been described in dogs, rats, rabbits and humans [7][8][9][10]. This drug is extensively metabolised by N-demethylation, N-dealkylation and Odemethylation [4,11].…”