Rectal bioavailability of lidocaine in man: Partial avoidance of “first‐pass” metabolism

It is often speculated that after rectal administration drugs will enter the systemic circulation without first passing through the liver, because at least the lower hemorrhoidal veins are not connected to the portal system. To test this hypothesis, the systemic availability of the high-clearance drug lidocaine was investigated in 6 healthy subjects following administration of 200 mg intravenous, 300 mg oral, and 300 mg rectal lidocaine in a balanced crossover design. Plasma and whole blood concentrations of lidocaine were measured by capillary gas chromatography. The mean rectal systemic availability was higher than the oral: 63% vs 31% (whole blood) and 71% vs 34% (plasma). The elimination half-lifes (t1/2els) lidocaine were about the same intravenously and orally, whereas these were slightly longer after rectal administration. The oral and rectal investigations were repeated in the same panel of volunteers about 6 mo later. The mean rectal systemic availability, based on plasma concentrations, was then 67% vs 27% orally. Intraindividual variability was rather small, indicating that oral and rectal bioavailability of lidocaine is reproducible in individuals. An equation was derived for the calculation of the fraction of the dose given rectally that bypasses the liver after absorption which is slightly more than half the dose, assuming that dose is 100% absorbed. This investigation indicates that in principle it is possible to avoid, at least partly, drug loss caused by "first-pass" metabolism by giving the drug rectally.