THE HYPOXIC VENTILLATORY RESPONSE AND HEPATIC CYP3A4 UPREGULATION IN HUMAN AT HIGH ALTITUDE

The Hypoxic Ventillatory Response (HVR) at high altitude was hypothesized to cause pharmacokinetics changes, especially metabolism of drugs due to the up regulation of CYP3A4 isoenzyme. These pharmacokinetic alteration could affect pharmacotherapy, probably lead to either sub therapeutic or supra therapeutic effects. This hypothesis was studied with a pop-PK study conducted in healthy male volunteers inhabited at geographically high altitude area. Firstly, the HVR was assessed by changes in partial pressures of blood gases, oxygen concentration in arterial blood, oxygen gradient in arterial-alveolar gas exchange and oxygen concentration of arterial blood. Secondly, the Probe drug Alprazolam 1mg oral single dose was given to find out the dysregulation of CYP3A4 and blood samples were analyzed for pharmacokinetic changes The pharmacokinetic variables such as C_max, T_max, AUC, K^el, MRT, t½ etc were significantly altered in study subjects. The C_max and AUC values were significantly reduced in HVR group than non HVR group (21.26 ±1.40, p<0.05). The elimination and clearance were significantly increased in hypoxia group (p<0.05) whereas the V^d was not affected. MRT and t½ was reduced the faster metabolism and elimination of drug. In conclusion, the metabolism was increased due to CYP3A4 upregulation and elimination was increased in hypoxia study subjects. Hence, this pharmacokinetic dose response pattern has to be considered for optimizing the dose of drugs metabolized by CYP3A4.