Abstract

Carbovir (CBV), a carbocyclic nucleoside analog, is a potent and selective inhibitor of human immunodeficiency virus in human T-cells at noncytotoxic concentrations. Previous pharmacokinetic studies of (-)CBV in the rat showed nonlinearity in both the renal and nonrenal clearances and an oral bioavailability of 20%. This study was designed to evaluate the contribution of the rat liver and intestine to the first-pass effect of (-)CBV. The elimination of (-)CBV by the rat liver and intestine and the saturability of these processes were investigated with recirculating in situ perfused rat liver and intestinal vasculature preparations. Male Sprague-Dawley rats were used as liver (N = 11) or intestine (N = 3) donors. The recirculating perfusion studies were conducted with initial (-)CBV inflow concentrations ranging between 1.0-50 micrograms/ml for the liver perfusions and between 0.15-2.5 micrograms/ml for the intestinal perfusions. The hepatic elimination of (-)CBV was linear in the concentration range studied, with an instantaneous extraction ratio of 0.104 +/- 0.026 and an intrinsic clearance of 1.09 +/- 0.41 ml/min. The rat intestine did not extract (-)CBV. These studies indicate that the rat liver and intestine are not responsible for either the nonlinearity in nonrenal clearance or the low oral bioavailability observed in vivo.