Disposition of (-)carbovir in the in situ perfused rat liver and intestinal vasculature preparations

I. Soria, C. L. Zimmerman

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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 μg/ml for the liver perfusions and between 0.15-2.5 μg/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.

Original languageEnglish (US)
Pages (from-to)724-729
Number of pages6
JournalDrug Metabolism and Disposition
Issue number4
StatePublished - Jan 1 1993


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