Abstract
Ritonavir (RTV) was used as a boosting agent to increase the clinical exposure of BILR 355, an inhibitor of the human immunodeficiency virus, by inhibiting the CYP3A-mediated metabolism of BILR 355. However, while the levels of BILR 355 increased upon concomitant administration of RTV, a metabolite of BILR 355, BILR 516, which was not detected previously in humans dosed with BILR 355 alone, became a disproportionate human metabolite with levels exceeding the parent levels at steady-state. This was an unusual finding based on in vitro and in vivo metabolic profiles of BILR 355 available at that time. Our studies reveal that BILR 355 is reduced to an intermediate, BILR 402, by gut bacteria and the reduced metabolite (BILR 402) is then oxidized by aldehyde oxidase to form BILR 516, the disproportionate human metabolite. The role of aldehyde oxidase helped to explain the somewhat unique formation of BILR 516 in humans compared to preclinical animal species. This paper underlines the increasing importance of two individually atypical enzymes in drug development, gut bacterial biotransformation and aldehyde oxidase, which in combination provided a unique metabolic pathway. In addition, this paper clearly elucidates an example of novel metabolic switching and, hopefully, raises awareness of the potential for metabolic switching in combination drug therapies.
- Received December 19, 2011.
- Accepted March 5, 2012.
- The American Society for Pharmacology and Experimental Therapeutics