Effect of 12-oxochenodeoxycholate on the pharmacokinetics and pharmacodynamics of morphine 6-glucuronide in Wistar rats.

The semi-synthetic bile salt, 12-oxochenodeoxycholate (OCDC also known as 12-monoketocholate), has been shown to enhance drug permeation across biological membranes with low cytotoxicity. Its effect on the analgesic potency and brain concentration of morphine 6-glucuronide (M6G) was studied in male Wistar rats. Four groups of animals (n = 8) were given 5, 10 or 20 mg/kg OCDC or normal saline (control) by subcutaneous injection 30 min before a subcutaneous injection of 5 mg/kg M6G after which the hotplate test was performed on each rat at various times. After a 2 week wash-out period, the same rats (n = 30) were randomized to two equal groups and given OCDC (20 mg/kg) or normal saline 30 min before 5 mg/kg M6G. At five time points up to 3 h after M6G administration, three rats from each group were euthanized and blood and brain analyzed for M6G. The area under the analgesic effect versus time curve (AUAE) was found to be significantly (P < 0.05) greater in rats given 20 mg/kg OCDC than in control rats. Area under the curve (AUC) for M6G in both plasma and brain was greater in OCDC-treated rats than in control rats, but the brain : plasma AUC ratio was lower. OCDC enhances the analgesic effect of M6G but gives a lower brain : plasma ratio due to increasing M6G plasma levels probably by reducing its renal clearance.