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

Abstract

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.

Spline functions in convolutional modeling of verapamil bioavailability and bioequivalence. II: Study in healthy volunteers

“…It is obligatory to comply with the GCP and GLP standards, with thorough record-keeping of the specificity, sensitivity, and precision of the methods used in the estimation of the product or its metabolites in the body fluids, and ensure that an accurate pharmacokinetic numerical and statistical evaluation of the data is made. The pharmacokinetic parameters for verapamil, determined in this studyfor a new retard tablet formulation of the drug, are in reasonable agreement with the data obtained earlier (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). The use of k for the extrapolation of AUC po ' as AUC po n-ee=Cik, overestimates AUC po n-f rom the flip-flop phenomenon of absorption (k~and the terminal phase of elimination (~) inversion of constants: k a <A 2 • Usage of A 2 , for the intravenous experiment, for the extrapolation of AUC po ' as AUC po n_~=Cn/ A 2 , underestimates AUC po n-~because absorption is not terminated at tn=24 h after p.o.…”

“…Verapamil exhibits bi-or triphasic elimination kinetics and is reported to have a terminal plasma half-life of 2 to 8 hours following a single oral (non-retard) dose or after intravenous administration (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). There is considerable interindividual variation reported in plasma concentrations, with peak plasma concentrations within 1 to 2 hours of oral administration.…”

Effects of verapamil on etoposide pharmacokinetics after intravenous and oral administration in rats

“…Verapamil is administered as a racemic mixture of the enantiomers. Both R-and S-verapamil are equally effective in modulating P-gp mediated drug transport in vitro (19), but the S-enantiomer is more cardioactive than R-verapamil (20). The coadministration of verapamil might constitute a possible approach to improve the erratic bioavailability of etoposide.…”

Mephenytoin stereoselective elimination in the rat: II. Comparison of mephenytoin stereoselective clearance during chronic intravenous and hepatic portal vein administration

“…Consequently, work is currently being carried out in many laboratories throughout the world to better characterize the stereoselective disposition and response to racemic therapeutic agents and to define the factor(s) which may affect such stereoselective processes (6)(7)(8)(9)(10).…”