INTRAVENOUS VERAPAMIL KINETICS IN RATS - MARKED ARTERIOVENOUS CONCENTRATION DIFFERENCE AND COMPARISON WITH HUMANS

The pharmacokinetics of verapamil, a calcium channel blocker, were stu died in male Sprague-Dawley rats following i.v. administration at a do se of 1 mg kg-1. Both arterial and venous blood were collected and the plasma drug concentrations were determined by reversed-phase high-per formance liquid chromatography. Verapamil was distributed to the extra vascular tissues very rapidly as indicated by the large V(dss) (2.99 /- 0.57 1 kg-1) and V(dbeta) (5.08 +/- 0.54 1 kg-1). The apparent term inal plasma T1/2, 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/ven ous differences were found with a considerable influence on the MRT an d V(dss), and the terminal phase venous levels were higher than arteri al levels by 103, 69, and 90%, respectively, for the three rats studie d. The distribution of verapamil between plasma and erythrocytes occur red very rapidly and was identical in vitro and in vivo. The average b lood 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 rat io of verapamil (0.87). The plasma protein binding of verapamil in hum ans (90%) and rats (95%) were quite similar and constant over the wide concentration range studied. A comparison of some pharmacokinetic par ameters between rats and humans is presented and the potential shortco mings of using T1/2 or CL(p) and the advantage of using CL(u) (unbound plasma clearance) in interspecies scaling is also discussed.