School of Pharmacy, University of Otago, Dunedin, New Zealand.
J Pharm Pharmacol. 2013 Apr;65(4):561-6. doi: 10.1111/jphp.12020. Epub 2013 Jan 16.
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.
半合成胆盐 12-氧代胆酸（OCDC，也称为 12-单酮胆酸）已被证明可在低细胞毒性的情况下增强药物透过生物膜的能力。本研究旨在观察 12-氧代胆酸对吗啡 6-葡萄糖醛酸（M6G）的镇痛效力和脑浓度的影响。
4 组雄性 Wistar 大鼠（n=8）分别于 30 min 前经皮下注射 5、10 或 20 mg/kg OCDC 或生理盐水（对照组），然后在每只大鼠皮下注射 5 mg/kg M6G 后，在不同时间点进行热板试验。在 2 周洗脱期后，将相同的大鼠（n=30）随机分为两组，分别给予 OCDC（20 mg/kg）或生理盐水，30 min 后给予 5 mg/kg M6G。在 M6G 给药后 5 个时间点，每组 3 只大鼠安乐死，分析血液和大脑中的 M6G。
与对照组相比，给予 20 mg/kg OCDC 的大鼠的镇痛效应 AUC0-t 显著增加（P<0.05）。OCDC 处理组大鼠的 M6G 在血浆和大脑中的 AUC 均大于对照组，但脑：血浆 AUC 比值较低。
OCDC 增强了 M6G 的镇痛效果，但由于增加了 M6G 的血浆水平，可能通过降低其肾清除率，导致脑：血浆 AUC 比值降低。
