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Biotransformation and mass balance of tipranavir, a nonpeptidic protease inhibitor, when co‐administered with ritonavir in Sprague‐Dawley rats

In this study, tipranavir (TPV) biotransformation and disposition when co‐administered with ritonavir (RTV) were characterized in Sprague–Dawley rats. Rats were administered a single intravenous (5 mg kg−1) or oral (10 mg kg−1) dose of [14C]TPV with co‐administration of RTV (10 mg kg−1). Blood, urine, faeces and bile samples were collected at specified time‐points over a period of 168 h. Absorption of TPV‐related radioactivity ranged from 53.2–59.6%. Faecal excretion was on average 86.7% and 82.4% (intravenous) and 75.0% and 82.0% (oral) of dosed radioactivity in males and females, respectively. Urinary excretion was on average 4.06% and 6.73% (intravenous) and 9.71% and 8.28% (oral) of dosed radioactivity in males and females, respectively. In bile‐duct‐cannulated rats, 39.8% of the dose was recovered in bile. After oral administration, unchanged TPV accounted for the majority of the radioactivity in plasma (85.7–96.3%), faeces (71.8–80.1%) and urine (33.3–62.3%). The most abundant metabolite in faeces was an oxidation metabolite R‐2 (5.9–7.4% of faecal radioactivity, 4.4–6.1% of dose). In urine, no single metabolite was found to be significant, and comprised <1% of dose. TPV when co‐administered with RTV to rats was mainly excreted in feces via bile and the parent compound was the major component in plasma and faeces.