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

  • Macha S
  • Chen L
  • Norris S
  • et al.
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Abstract

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.

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Macha, S., Chen, L., Norris, S. H., Philip, E., Mao, Y., Silverstein, H., … Beers, W. (2010). Biotransformation and mass balance of tipranavir, a nonpeptidic protease inhibitor, when co-administered with ritonavir in Sprague-Dawley rats. Journal of Pharmacy and Pharmacology, 59(9), 1223–1233. https://doi.org/10.1211/jpp.59.9.0006

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