title: Hepatic metabolism of ibuprofen in rats under acute hypobaric hypoxia.
abstract: Hypobaric hypoxia induced at high altitude causes a subnormal oxygen concentration in cells which affects the drug metabolic and pharmacokinetic (PK) capacity of the body. The metabolism and PK of drugs like ibuprofen may be impaired under hypoxia and may require a different than usual therapeutic dose regimen to ensure safe therapy. The present investigation was undertaken to evaluate the effect of acute hypobaric hypoxia (AHH) on hepatic metabolism and PK of ibuprofen in rats. Animals were exposed to simulated altitude of 7620 m (∼25,000 ft) for AHH exposure (6 and 24 h) in a decompression chamber and were administrated with single dose of ibuprofen (80 mg/kg body weight, p.o.). The results showed that GST activity was significantly reduced at 6 h (15%) and 24 h (23%) (p<0.05) in hypoxic group as compared to normoxic. A significant increase by 20-24% (p<0.05) in AST level was observed after AHH exposure. LDH activity also exhibited significant increase (p<0.05) after 24h of AHH. A significant down-regulated CYP2C9 level and mild histopathological changes were observed after 24h of AHH. Furthermore, PK variables viz. elimination half-life (T½) and mean residence time (MRT) of ibuprofen exhibited significant increase by 42% and 51% (p<0.05) respectively after 24h of AHH. Thus, results suggest that AHH exposure of 24h significantly affects phase II conjugation pathway, CYP2C9 level, AST level, liver histology and PK parameters. This asserts that AHH can impair disposition of ibuprofen however, it requires further investigation under chronic hypobaric hypoxic conditions.
authors.affiliation: Defence Institute of Physiology and Allied Sciences, DRDO, Lucknow Road, Timarpur, Delhi 110 054, India.
authors.forename: Shefali
authors.initials: S
authors.lastname: Gola
authors.forename: Gaurav Km
authors.initials: GK
authors.lastname: Keshri
authors.forename: Asheesh
authors.initials: A
authors.lastname: Gupta
mesh_terms: D000208:Acute Disease; D000531:Altitude; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005978:Glutathione / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D007052:Ibuprofen / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003577:Cytochrome P-450 Enzyme System; C507848:CYP2C9 protein, rat; D005978:Glutathione; D010100:Oxygen; D007052:Ibuprofen