EVIDENCE FOR P-GLYCOPROTEIN-MODULATED PENETRATION OF MORPHINE-6-GLUCURONIDE INTO BRAIN CAPILLARY ENDOTHELIUM

1 Morphine-6-glucuronide is one of the major metabolites of morphine. The potent analgesic action of this compound together with its potenti al lower apparent toxicity in man, when compared with morphine, indica ted its clinical importance. 2 Primary cultures of porcine brain capil lary endothelial cells were used to study brain penetration of morphin e-6-glucuronide. Biochemical characterization of the cell cultures rev ealed a marked enrichment in enzymatic activity of alkaline phosphatas e (56 fold) and angiotensin converting enzyme (230 fold) as compared t o whole brain tissue. By immunostaining the presence of vimentin, fact or VIII, the tight junction associated protein ZO-1, and P-glycoprotei n was shown. Functional characterization revealed that the carrier sys tem responsible for transport of neutral amino acids was intact. 3 Upt ake and transport of morphine-6-glucuronide was marginal and in the ra nge of the extracellular marker sucrose. However, uptake of morphine-6 -glucuronide was enhanced significantly (P<0.0001) in presence of the inhibitors of P-glycoprotein, verapamil or vincristine. The finding th at morphine-6-glucuronide may serve as a substrate for P-glycoprotein was confirmed in multidrug-resistant P388 tumour cells. 4 We conclude that penetration of the blood-brain barrier by morphine-6-glucuronide may depend on the expression of the product of the multidrug-resistanc e (MDR) gene in brain capillary endothelial cells.