Cytochrome P450 enzyme-mediated drug metabolism at exposure to acute hypoxia (corresponding to an altitude of 4,500 m)

Abstract

Objective: To investigate the effect of acute hypoxia and concomitant changes in portal blood flow on the disposition of drugs mainly metabolized by the cytochrome P(450) enzymes (CYP) 3A4 (verapamil) and CYP1A2 (theophylline).

Methods: Twenty healthy male participants were studied on two 14-h study days in a normobaric hypoxic chamber and were allocated randomly to one of two groups receiving short infusions of either theophylline (6 mg kg (-1) body weight) or verapamil (5 mg) intravenously. According to a randomized, cross-over design, participants were once exposed to normoxia and once to hypoxia (12% oxygen corresponding to the ambient( P)O(2) at an altitude of 4,500 m above sea level). The concentrations of theophylline, 1,3-dimethyluric acid, verapamil, and norverapamil were determined in serial blood samples by means of liquid chromatography-mass spectrometry (LC/MS/MS). Portal blood flow was assessed by transabdominal duplex ultrasonography.

Results: Acute hypoxia did not alter the pharmacokinetics of theophylline [half-life+/-SD: 9.29+/-1.77 versus 9.39+/-1.40 (hypoxia)], 1,3-dimethyluric acid (12.9+/-4.72 versus 15.1+/-8.59), verapamil (2.00+/-0.98 versus 1.79+/-0.58), or norverapamil (7.98+/-2.94 versus 9.91+/-6.40). Individual changes of elimination half-life and changes in capillary oxygen saturation,( P)O(2), or portal vein flow were not correlated. Portal vein flow was unaffected by hypoxia.

Conclusions: Acute hypoxia corresponding to hypoxia at altitudes of 4,500 m does not impair the metabolism mediated by CYP1A2 or CYP3A4. At rapid ascent to and short-term stay at altitudes up to 4,500 m, the doses of drugs metabolized by these CYPs do therefore not require dose modification, and major changes in the disposition of already administered drugs are not to be expected.