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Intravenous verapamil kinetics in rats: Marked arteriovenous concentration difference and comparison with humans
Author(s) -
Manitpisitkul Prasarn,
Chiou Win L.
Publication year - 1993
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510140702
Subject(s) - verapamil , pharmacokinetics , venous blood , in vivo , chemistry , propranolol , blood plasma , distribution (mathematics) , endocrinology , pharmacology , medicine , calcium , biology , mathematical analysis , microbiology and biotechnology , mathematics
The pharmacokinetics of verapamil, a calcium channel blocker, were studied in male Sprague—Dawley rats following i.v. administration at a dose of 1 mg kg −1 . Both arterial and venous blood were collected and the plasma drug concentrations were determined by reversed‐phase high‐performance liquid chromatography. Verapamil was distributed to the extravascular tissues very rapidly as indicated by the large V dss (2.99±0.57 1 kg −1 ) and V dβ (5.08 ± 0.541 kg −1 ). The apparent terminal plasma T 1/2 , MRT iv , and CL p were 1.59 ± 0.46, 1.26 ± 0.12 h, and 40.4 ± 9.73 ml min −1 kg −1 , respectively. Marked arterial/venous differences were found with a considerable influence on the MRT and V dss , and the terminal phase venous levels were higher than arterial levels by 103, 69, and 90%, respectively, for the three rats studied. The distribution of verapamil between plasma and erythrocytes occurred very rapidly and was identical in vitro and in vivo . The average blood to plasma and plasma to blood cell concentration ratios were 0.85 and 1.47, respectively. In contrast to propranolol, blood data rather than plasma data should be used to predict the hepatic extraction ratio of verapamil (0.87). The plasma protein binding of verapamil in humans (90%) and rats (95%) were quite similar and constant over the wide concentration range studied. A comparison of some pharmacokinetic parameters between rats and humans is presented and the potential shortcomings of using T 1/2 or CL p and the advantage of using CL u (unbound plasma clearance) in interspecies scaling is also discussed.