Effect of omeprazole on oral and intravenous RS-methadone pharmacokinetics and pharmacodynamics in the rat.
The effect of omeprazole on oral and intravenous (iv) RS-methadone pharmacokinetics and pharmacodynamics was studied in awake, freely moving rats, which were divided in four groups: oral RS-methadone (3 mg/kg) was given (a) to a control group (CO(oral)) (n = 65) and (b) to an omeprazole pretreated group (OP(oral)) (n = 77), and iv RS-methadone (0.35 mg/kg) was administered (c) to a control group (CO(iv)) (n = 86) and (d) to an omeprazole pretreated group (OP(iv)) (n = 86). Omeprazole (2 mg/kg) was given iv 2 h before RS-methadone. Plasma concentrations of RS-methadone (Cp) were determined by high-performance liquid chromatography and analgesic response by tail flick for 0-180 min (oral) and 0-120 min (iv). RS-Methadone rate of absorption (mean +/- SE) was faster in OP(oral) (k(01) = 0.31 +/- 0.04 min(-1)) than in CO(oral) (k(01) = 0.05 +/- 0.007 min(-1)), consequently plasma peak concentrations (C(max)) were greater (197.41 +/- 33.70 ng/mL versus 83.54 +/- 7.97 ng/mL) and the time to reach C(max) (t(max)) was shorter (11.23 +/- 1.32 min versus 39.18 +/- 1.74 min). Mean area under the Cp-time curve (AUC(0-infinity)) and hence bioavailability of oral RS-methadone were increased by omeprazole without significant changes in the elimination. Omeprazole did not affect the pharmacokinetics of iv RS-methadone. The changes of the analgesic effect of RS-methadone as a function of time were similar in all four groups. In the CO(oral) group, Cp and analgesic effect were defined by the E(max) model. The relationship between Cp and drug effect in the OP(oral) group showed a counterclockwise hysteresis (k(e0) of 0.018 +/- 0.006 min(-1)). For the iv groups (CO(iv) and OP(iv)), the Cp-analgesic effect relationship was described by an E(max) sigmoid model and omeprazole did not affect the pharmacodynamic parameters. It is concluded that omeprazole causes an increase in the bioavailability of oral RS-methadone without modifying the analgesic response but affecting the Cp-effect relationship.
Carlos
M Angeles
MA
Department of Pharmacology, School of Medicine, University of the Basque Country, Leioa, 48940 Spain.
Du Souich
Patrick
P
Carlos
Raimundo
R
Suarez
Elena
E
Lukas
John C
JC
Calvo
Rosario
R
D000284:Administration, Oral; D000818:Animals; D004357:Drug Synergism; D005260:Female; D007275:Injections, Intravenous; D008691:Methadone / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D009853:Omeprazole / Q000493:pharmacokinetics* / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D009853:Omeprazole; D008691:Methadone