Effect of nifedipine on the elimination of theophylline in the rabbit subjected to hypoxia or to an inflammatory reaction.
This study was performed to assess whether nifedipine could prevent the decrease in hepatic cytochrome P450 induced by acute moderate hypoxia or an inflammatory reaction. Rabbits were subjected to acute moderate hypoxia (PaO2 > 37 mmHg), with or without pretreatment with nifedipine (0.5 mg kg-1 subcutaneously every 8 h, for 48 h). Another group received 5 mL of turpentine subcutaneously with or without pretreatment with nifedipine (0.5 mg kg-1 s.c. every 8 h, for 72 h). The kinetics of 2.5 mg kg-1 of theophylline were studied in all rabbits up to 8 h, at which time total cytochrome P450 and malondialdehyde were assessed in the liver. Compared with control rabbits, hypoxia and an inflammatory reaction increased theophylline plasma concentrations, as a result of 3 decrease in theophylline systemic clearance. Both experimental conditions reduced hepatic cytochrome P450 by 40 to 50% and increased hepatic malondialdehyde by approximately 50% (P < 0.05). In control animals, pretreatment with nifedipine did not influence theophylline kinetics, the liver content in cytochrome P450 or malondialdehyde. Pretreatment with nifedipine partially prevented the hypoxia- and the inflammation-induced decrease in liver cytochrome P450; however, nifedipine did not prevent the decrease in theophylline clearance or the increase in liver malondialdehyde. It is concluded that nifedipine affords a partial protection against hypoxia- or inflammation-induced hepatic cellular injury.
Department of Pharmacology, Faculty of Medicine, University of Montréal, Québec, Canada.
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Barakat
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du Souich
D000818:Animals; D019540:Area Under Curve; D001993:Bronchodilator Agents / Q000493:pharmacokinetics*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006207:Half-Life; D000860:Hypoxia / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007509:Irritants; D008099:Liver / Q000201:enzymology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D011817:Rabbits; D013806:Theophylline / Q000493:pharmacokinetics*; D014425:Turpentine
D001993:Bronchodilator Agents; D002121:Calcium Channel Blockers; D007509:Irritants; D008315:Malondialdehyde; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D009543:Nifedipine; D014425:Turpentine