TRIAZOLAM PHARMACOKINETICS AFTER INTRAVENOUS, ORAL, AND SUBLINGUAL ADMINISTRATION

This study was designed to evaluate the relative and absolute bioavail ability of triazolam, 0.25 mg, after the administration of the markete d oral tablet and a sublingual prototype wafer; an intravenous dose wa s used as a reference, Twelve men were evaluated in a three-way crosso ver study; study days were separated by 1 week, A single dose was admi nistered to each subject at approximately 8 a.m.; serial blood samples were obtained for the determination of triazolam concentration, The f raction absorbed relative to intravenous was 20% higher in the subling ual than in the oral treatment (p = 0.0128); the difference between tr eatments was greatest in the first 2 hours as indicated by the area un der the curve from 0 to 2 hours (p < 0.05). The extraction ratio range d from 0.05 to 0.25, and the predicted availability after oral adminis tration was 86% with a range of 75 to 95%. In contrast, the observed m ean absolute availability was 44% (oral) and 53% (sublingual). A poten tial explanation for this discrepancy between predicted and observed b ioavailability is that after oral administration, a fraction of triazo lam may be metabolized by cytochrome P450IIIA4 in the gut wall, with a separate fraction subject to first-pass metabolism in the liver, Alth ough this study was not designed to identify sites of triazolam metabo lism, the proposed explanation is consistent with the occurrence of P4 50IIIA4 in the stomach, small intestine, and liver, Doses administered sublingually avoid first-pass metabolism, producing earlier and highe r peak concentrations than do doses administered orally.