Hepatic uptake and metabolism of pentacaine: a study with microsomes, hepatocytes and perfused livers of rats.

The uptake and metabolism of pentacaine, a novel carbanilate local anaesthetic agent, were studied using different rat-liver preparations. Pentacaine, added to a rat-liver microsomal suspension, elicited a type-I spectrum with Ks of 2.3 microM. The Km for total metabolism of pentacaine by rat-liver microsomes was 33.5 microM and in isolated hepatocytes 19.1 microM. Good agreement was obtained between the Vmax values for both in vitro systems and for perfused rat liver. In an isolated perfused rat liver the mean extraction ratio of pentacaine was 0.99 for a single pass, but it was significantly decreased by the presence of albumin and red blood cells. The uptake of pentacaine by isolated hepatocytes was rapid and independent of drug concn. over the range 0-200 microM. The high hepatic extraction of pentacaine is probably due mostly to passive diffusion and non-specific intracellular binding; metabolic elimination is secondary and much slower than uptake. The extensive first-pass removal of free pentacaine suggests that the systemic fraction of an oral dose in vivo is derived mainly from drug bound to blood components.