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METABOLISM AND EXCRETION OF CAPRAVIRINE, A NEW NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR, ALONE AND IN COMBINATION WITH RITONAVIR IN HEALTHY VOLUNTEERS

Departments of Pharmacokinetics, Dynamics & Metabolism (H.-Z.B.,W.F.P., E.Y.W., B.V.S.) and Clinical Research (S.R.R., M.A.A.), Pfizer Global Research and Development, San Diego, California

Metabolism and disposition of capravirine, a new non-nucleoside reverse transcriptase inhibitor, were studied in healthy male volunteers who were randomly divided into two groups (A and B) with five subjects in each group. Group A received a single oral dose of [¹⁴C]capravirine (1400 mg) and group B received multiple oral doses of ritonavir (100 mg), followed by a single oral dose of [¹⁴C]capravirine (1400 mg). Mean total recoveries of radioactivity for groups A and B were 86.3% and 79.0%, respectively, with a mean cumulative recovery in urine comparable with that in feces for both groups. Excretion of unchanged capravirine was negligible in urine and low in feces for both groups. The results suggest that capravirine was well absorbed, with metabolism as the principal mechanism of clearance. Capravirine underwent extensive metabolism to a variety of metabolites via oxygenations (mono-, di-, tri-, and tetra-) representing the predominant pathway, glucuronidation, and sulfation in humans. No useful plasma profiles of group A were obtained due to extremely low levels of plasma radioactivity. Analysis of group B plasma indicated that unchanged capravirine was the major radiochemical component, with three monooxygenated products and a glucuronide of capravirine as the major circulating metabolites. Nineteen metabolites were identified using liquid chromatography-multistage ion-trap mass spectrometry methodologies. In summary, coadministration of low-dose ritonavir (a potent CYP3A4 inhibitor) drastically decreased the levels of sequential oxygenated metabolites and markedly increased the levels of the parent drug and primary oxygenated metabolites overall in plasma, urine, and feces.

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