Intravenous epoprostenol sodium does not increase hepatic microsomal enzyme activity in rats.
Previous studies have indicated that epoprostenol may increase hepatic microsomal enzyme activity both in animals and humans. However, interpretation of the results of these studies may be confounded by the route of epoprostenol administration or small sample sizes. The primary objective of the present investigation was to evaluate the effects of epoprostenol (given as a continuous intravenous infusion) on hepatic microsomal enzyme activity in rats. Male Sprague Dawley rats (220-290 g) received infusions of either vehicle (glycine buffer, 1 mL/hr) or 0.2 microgram/kg/min epoprostenol through a jugular vein cannula for 24 hr or 7 days. At the end of the infusion, a 25 mg/kg i.v. bolus of antipyrine was administered and blood samples were collected over 6 hr. Serum antipyrine concentrations were determined by HPLC. Twenty-four hr post-infusion, hepatic microsomes were prepared, and cytochrome P-450 content was determined by difference spectroscopy. Cytochrome P-450 content and antipyrine clearance values determined from serum antipyrine concentration-time profiles were not significantly different between treatment groups. Antipyrine clearance [mean (SD)] in the 24-hr vehicle-treated group was 3.68 (0.49) mL/min/kg versus 4.35 (1.1)mL/min/kg in the epoprostenol-treated group. In the 7-day vehicle-treated rats, antipyrine clearance was 5.43 (1.0) mL/min/kg compared to 4.68 (0.61) mL/min/kg in epoprostenol-treated rats. A statistically significant effect of infusion duration was observed in the control group, i.e., antipyrine clearance in rats treated with vehicle for 7 days was significantly greater than that observed in rats treated with vehicle for 24 hr. However, the increase was less than 50%. These data suggest that when epoprostenol is administered as an intravenous infusion to rats, no significant alterations in hepatic microsomal enzyme activity occur. Based on these data, long term changes in hepatic metabolism in response to chronic epoprostenol administration are not expected.
Carlton
L D
LD
Department of Clinical Pharmacokinetics/Dynamics, Burroughs Wellcome Co., Research Triangle Park, N.C., USA.
Schmith
V D
VD
Brouwer
K L
KL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000983:Antipyrine / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism; D011464:Epoprostenol / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010975:Platelet Aggregation Inhibitors; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D000983:Antipyrine