Verapamil disposition kinetics in chronic atrial fibrillation

1 The effect of verapamil pre-treatment on the pharmacokinetics and metabolism of antipyrine was studied in eight healthy male volunteers. 2 The oral clearance of antipyrine was decreased from 2.18 to 1.95 1 h-'1 (P < 0.01) by verapamil (80 mg three times daily for 2 days prior to antipyrine administration and 2 days following) while half-life was increased from 13.2 to 15.6 h (P < 0.01). 3 The urinary excretion of norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was decreased by 19.2%, 23.1% and 16.7% respectively (P < 0.05) in the presence of verapamil. In addition, the rate constants for formation of each of these metabolites were significantly decreased by an average of approximately 30%. 4 These results suggest that verapamil is capable of inhibiting oxidative metabolism, a finding which could be of clinical significance for drugs highly dependent upon pathways such as those inhibited in this study for elimination.

Section: Introductionmentioning

confidence: 95%

The effect of verapamil on antipyrine pharmacokinetics and metabolism in man.

Bach¹,

Blevins²,

Kerner³

et al. 1986

“…Following intravenous administration, the systemic clearance of verapamil is high and approaches hepatic blood flow. Due to this high hepatic extraction, verapamil undergoes extensive 'first-pass' elimination when given orally and therefore despite its almost complete absorption absolute bioavailability is on average only 20-30% (Schomerus etal., 1976;Eichelbaum et al, , 1981aFreedman et al, 1981;Johnston et al, 1981; Kates et al, 1981;Somogyi etal., 1981;Woodcock etal., 1981a, b;Anderson et al, 1982). The drug preparation available for clinical use is a racemic mixture of the (+)-and (-)-isomer.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of (+)‐, (‐)‐ and (+/‐)‐verapamil after intravenous administration.

Eichelbaum¹,

Mikus²,

Vogelgesang³

1984

174

The pharmacokinetics of (+)‐, (‐)‐, and (+/‐)‐verapamil were studied in five healthy volunteers following i.v. administration of the drugs. Pronounced differences of the various pharmacokinetic parameters were observed between the (‐)‐ and (+)‐isomers. The values for CL, V, Vz, and Vss of the (‐)‐isomer were substantially higher as compared to the (+)‐isomer, whereas terminal t 1/ 2Z was nearly identical for both isomers. No dose dependency of the pharmacokinetics could be observed in two subjects who received 5, 7.5 and 10 mg of (‐)‐ and 5, 25 and 50 mg of (+)‐verapamil. Protein binding for the two isomers was also different. The fu of (‐)‐ (0.11) was almost twice as much as that of (+)‐verapamil (0.064). Pharmacokinetic parameters of (+/‐)‐verapamil, which was administered to three subjects who had received (+)‐ and (‐)‐ verapamil, were very similar to the averaged values of the isomers given separately. Due to the higher CL of (‐)‐verapamil the extraction ratio of the (‐)‐isomer is substantially higher. Thus, it can be anticipated that following oral administration of racemic verapamil bioavailability of (‐)‐verapamil will be substantially less. Since the (‐)‐isomer is more potent than the (+)‐isomer, the present findings could explain the reported differences in the concentration‐effect relationship after i.v. and oral administration of racemic verapamil.

“…doses of 5 to 10 mg. pass metabolism (Schomerus et al, 1976; Eichel-However, oral doses 10 to 15 times greater than baum et Freedman et al, 1981;i.v. doses are usually required to produce Kates et al, 1981;Anderson et al, 1982; comparable clinical effects (Singh et al, 1983). McAllister et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Stereoselective first‐pass metabolism of highly cleared drugs: studies of the bioavailability of L‐ and D‐verapamil examined with a stable isotope technique.

Vogelgesang¹,

Echizen²,

Schmidt³

et al. 1984

167

The pharmacokinetics of dextro(+)‐ and levo(‐)‐verapamil were studied in five healthy volunteers following oral administration of pseudoracemic verapamil containing equal amounts of unlabelled (‐)‐ and dideuterated (+)‐isomer. (+)‐verapamil exhibited approximately five times greater Cmax (+): 240 +/‐ 81.1 ng/ml, (‐): 46.1 +/‐ 15.7 ng/ml, P less than 0.0001) and AUC than (‐)‐verapamil. The apparent oral clearance (CLo) for (+)‐verapamil was significantly smaller than that for (‐)‐verapamil (+): 1.72 +/‐ 0.57 l/min, (‐): 7.46 +/‐ 2.16 l/min, P less than 0.001). The bioavailability of (+)‐verapamil (50%) was 2.5 times greater than that of (‐)‐verapamil (20%), P less than 0.005). Thus following oral administration verapamil exhibited a stereoselective first‐pass metabolism. Neither tmax nor the elimination t1/2,z were different between the isomers. The elimination of t1/2,z for each verapamil isomer obtained following oral administration (+): 4.03 h, (‐): 5.38 h) were similar to those previously obtained following intravenous administration (+): 4.15 h, (‐): 5.38 h, respectively. Whereas the (+)‐ to (‐)‐verapamil plasma concentration ratio following oral administration was 4.92 +/‐ 0.48, the ratio following i.v. administration was approximately 2. (‐)‐verapamil has been demonstrated to possess 8 to 10 times more potent negative dromotropic effect on AV conduction than (+)‐verapamil. Therefore, following oral administration the same concentration of plasma verapamil consisting of a two to three times smaller proportion of the more potent (‐)‐isomer appeared to be less potent than that following i.v. administration with regard to the negative dromotropic effects on the AV conduction.