The Journal of pharmacy and pharmacology · 2013
Effect of 12-oxochenodeoxycholate on the pharmacokinetics and pharmacodynamics of morphine 6-glucuronide in Wistar rats.
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Yang Lin, Fawcett J Paul, Zhang Hu, Tucker Ian G
Аннотация
OBJECTIVES: 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.
METHODS: 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.
KEY FINDINGS: 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.
CONCLUSIONS: 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.
METHODS: 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.
KEY FINDINGS: 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.
CONCLUSIONS: 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.
Предметные рубрики MeSH
Analgesics, OpioidAnimalsBlood-Brain BarrierBrainChenodeoxycholic AcidDose-Response Relationship, DrugDrug SynergismInjections, SubcutaneousMaleMembrane Transport ModulatorsMetabolic Clearance RateMorphine DerivativesNeuronsPain MeasurementPermeabilityRandom AllocationRatsRats, WistarTissue Distribution