Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude

• Published in: Journal of pharmaceutical and biomedical analysis 2016-03, Vol.121, p.114-122
• Main Authors: Gola, Shefali, Gupta, Asheesh, Keshri, Gaurav K., Nath, Madhu, Velpandian, Thirumurthy
• Format: Article
• Language: English
• Subjects: Altitude; Animals; Area Under Curve; Chronic hypobaric hypoxia; CYP2C9; Cytochrome P-450 CYP2C9 - metabolism; Cytokines - metabolism; Down-Regulation - drug effects; Hepatic metabolism; Hypoxia - metabolism; Ibuprofen; Ibuprofen - pharmacokinetics; Inflammation - metabolism; Liver - metabolism; Male; Molecular Targeted Therapy - methods; Pharmacokinetics; Rats; Rats, Sprague-Dawley
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2016.01.018

[Display omitted] •High altitude-induced chronic hypobaric hypoxia (CHH) largely influence DMPK of ibuprofen.•Hepatic histopathological and toxicological evidences indicate damage under CHH.•CHH impaired phase I metabolism is chiefly associated with CYP2C9 down-regulation.•Enhanced cytokines expression can be responsible for CYP2C9 down-regulation.•Altered DMPK of ibuprofen signifies hindered safe and effective therapy under CHH. 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 7620m (∼25,000ft) for CHH exposure (7 or 14 days) in decompression chamber and administered with ibuprofen (80mg/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.