title: Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude.
abstract: With studies indicative of altered drug metabolism and pharmacokinetics (DMPK) under high altitude (HA)-induced hypobaric hypoxia, consideration of better therapeutic approaches has continuously been aimed in research for HA related illness management. DMPK of drugs like ibuprofen may get affected under hypoxia which establishes the requirement of different therapeutic dose regimen to ensure safe and effective therapy at HA. This study examined the effects of the chronic hypobaric hypoxia (CHH) on hepatic DMPK of ibuprofen in rats. Experimental animals were exposed to simulated altitude of 7620 m (∼25,000 ft) for CHH exposure (7 or 14 days) in decompression chamber and administered with ibuprofen (80 mg/kg, body weight, p.o.). Results demonstrated that CHH significantly altered PK variables of ibuprofen and activities of both phase-I and II hepatic metabolic enzymes as compared to the animals under normoxic conditions. Hepatic histopathological observations also revealed marked alterations. Increase in pro-inflammatory cytokines/chemokines viz. IL-1β, IL-2, IFN-γ, TNF-α exhibited close relevance with diminished CYP2C9 expression under CHH. Moreover, the down-regulated CYP2C9 level further supported the underlying mechanism for reduced metabolism of ibuprofen and as a result, increased retention of parent drug in the system. Increased mean retention time, Vd, T½ of ibuprofen, and decreased AUC, Cmax and clearance during CHH further strengthened the present findings. In conclusion, CHH exposure significantly affects hepatic DMPK of ibuprofen, which may further influence the usual therapeutic dose-regimen. Further, there is requirement of human studies to evaluate their susceptibility toward hypobaric hypoxia.
authors.affiliation: Department of Pharmacology, Defence Institute of Physiology and Allied Sciences (DIPAS), DRDO, Lucknow Road, Timarpur, Delhi 110054, India.
authors.forename: Shefali
authors.initials: S
authors.lastname: Gola
authors.affiliation: Department of Pharmacology, Defence Institute of Physiology and Allied Sciences (DIPAS), DRDO, Lucknow Road, Timarpur, Delhi 110054, India. Electronic address: asheeshgupta2001@gmail.com.
authors.forename: Asheesh
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Pharmacology, Defence Institute of Physiology and Allied Sciences (DIPAS), DRDO, Lucknow Road, Timarpur, Delhi 110054, India.
authors.forename: Gaurav K
authors.initials: GK
authors.lastname: Keshri
authors.affiliation: Pharmacokinetic Laboratory, Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.
authors.forename: Madhu
authors.initials: M
authors.lastname: Nath
authors.affiliation: Pharmacokinetic Laboratory, Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.
authors.forename: Thirumurthy
authors.initials: T
authors.lastname: Velpandian
mesh_terms: D000531:Altitude; D000818:Animals; D019540:Area Under Curve; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism*; D007052:Ibuprofen / Q000493:pharmacokinetics*; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D065729:Cytochrome P-450 CYP2C9; D007052:Ibuprofen
keywords: CYP2C9; Chronic hypobaric hypoxia; Hepatic metabolism; Ibuprofen; Pharmacokinetics