Background: Cytochrome-P450 enzymes metabolize most administered drugs. A variety of clinical conditions affect the CYP system. However, the effect of hemorrhagic shock on CYP-mediated drug metabolism in clinical setting or in clinically applicable in-vivo models is largely unknown. Simultaneous administration of multiple CYP enzyme-selective drugs is a technique to ascertain a population's metabolic profile with a limited number of subjects. Materials and Methods: Pigs were used as experimental animals as they possess CYP functionality similar to humans. Three probe drugs (dextromethorphan [CYP2D6], flurbiprofen [CYP2C9], and midazolam [CYP3A4]; doses: 0.5, 0.25, and 0.5 mg/kg, respectively) were administered intravenously to six Yorkshire-crossbred pigs in healthy state. Hemorrhagic shock was induced in six (four from healthy group after a 7-d washout period and two additional) pigs and the same doses of probe drugs were administered after a 14-h resuscitation phase. Blood samples were collected periodically in both phases and analyzed for parent drugs and metabolites (dextrorphan, 4'-hydroxy-flurbiprofen and 1'-hydroxy-midazolam) to calculate pharmacokinetic parameters. A comprehensive set of biochemical and physiologic markers of shock was also recorded. Results: No changes in parent drug clearances were observed post-shock. Extensive metabolite formation with apparent higher exposure to total (conjugated and unconjugated) dextrorphan (p = 0.08), 4'-hydroxy-flurbiprofen (p = 0.11) and 1'-hydroxy-midazolam (p = 0.09) were observed post-shock. Conclusions: The metabolic capacity of CYP enzymes did not appear to be severely hindered in resuscitative phase of hemorrhagic shock. Diminished renal secretory function caused by hemorrhagic shock may be the cause of metabolite accumulation in plasma.
Bibliographical noteFunding Information:
This work was funded by the Office of Naval Research (Grant N0001-14-02-1-0093 ). The authors thank Kristine Mulier and Dr David Skarda for conduct of surgical procedures. The help of Michele (Mickey) Dunning and personnel at the Experimental Surgical Services of the University of Minnesota in conduct of pig experiments is greatly appreciated. The authors also thank Dr Amit Khatri for his valuable assistance in analysis of pharmacokinetic data.