Effect of omeprazole on oral and intravenous RS‐methadone pharmacokinetics and pharmacodynamics in the rat

• Published in: Journal of pharmaceutical sciences Vol. 91; no. 7; pp. 1627 - 1638
• Main Authors: Carlos, M. Angeles, Souich, Patrick Du, Carlos, Raimundo, Suarez, Elena, Lukas, John C., Calvo, Rosario
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.07.2002; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Administration, Oral; analgesia; Analgesics; Animals; Biological and medical sciences; Digestive system; Drug Synergism; Female; Injections, Intravenous; Medical sciences; methadone; Methadone - administration & dosage; Methadone - blood; Methadone - pharmacokinetics; Neuropharmacology; omeprazole; Omeprazole - pharmacokinetics; Omeprazole - pharmacology; Pain Measurement - drug effects; pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; pharmacokinetics; omeprazole; methadone; analgesia; Stomach; Pharmacokinetic pharmacodynamic relationship; Drug combination; Intravenous administration; Rat; Digestive system; Rodentia; Oral administration; Opiates; Antiulcer agent; Methadone; Blood; Proton pump inhibitor; Blood plasma; Omeprazole; Vertebrata; Mammalia; Analgesic; Benzimidazole derivatives; Animal; pH; Drug interaction; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10031

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 (COoral) (n = 65) and (b) to an omeprazole pretreated group (OPoral) (n = 77), and iv RS‐methadone (0.35 mg/kg) was administered (c) to a control group (COiv) (n = 86) and (d) to an omeprazole pretreated group (OPiv) (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 0–180min (oral) and 0–120min (iv). RS‐Methadone rate of absorption (mean ± SE) was faster in OPoral (k01 = 0.31 ± 0.04min−1) than in COoral (k01 = 0.05 ± 0.007min−1), consequently plasma peak concentrations (Cmax) were greater (197.41 ± 33.70 ng/mL versus 83.54 ± 7.97 ng/mL) and the time to reach Cmax (tmax) was shorter (11.23 ± 1.32min versus 39.18 ± 1.74min). Mean area under the Cp‐time curve (AUC0–∞) 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 COoral group, Cp and analgesic effect were defined by the Emax model. The relationship between Cp and drug effect in the OPoral group showed a counterclockwise hysteresis (ke0 of 0.018 ± 0.006min−1). For the iv groups (COiv and OPiv), the Cp‐analgesic effect relationship was described by an Emax 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. © 2002 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:1627–1638, 2002