The effect of old age on the disposition and antinociceptive response of morphine and morphine-6 beta-glucuronide in the rat.

The aims of this study were to examine the effect of old age on the pharmacokinetics of morphine and morphine-6 beta-glucuronide (M6G) and their relationships to antinociceptive activity. Morphine (21.0 mumol/kg) or M6G (21.7 mumol/kg) were administered s.c. to young adult and aged male Hooded-Wistar rats. Antinociceptive effect was measured by the tail-flick method at various times up to 2.5 h or 6.5 h after morphine or M6G administration, respectively, and concentrations of morphine, morphine-3 beta-glucuronide (M3G) and M6G in plasma and brain were determined by HPLC. Creatinine clearance was significantly lower by 33% or 21% in aged compared to young adult rats receiving morphine or M6G, respectively. After morphine administration, the areas under the (i) antinociceptive effect-time curve, (ii) plasma morphine concentration-time curve, and (iii) brain morphine concentration-time curve were not different between young adult and aged rats. However, the AUC for plasma M3G was five-fold higher in the aged relative to young adult rats, which could not be accounted for by only a 33% lower creatinine clearance. M6G was not detected in any plasma or brain sample from rats administered morphine and no M3G was detected in brain. For M6G administration, the areas under the (i) antinociceptive effect-time curve, and (ii) plasma M6G concentration-time curve were 1.8- and 1.6-fold higher in aged compared to young adult rats, respectively. Concentrations of M6G in brain were below the limit of quantification. No morphine or M3G was detected in any of the plasma or brain samples of rats administered M6G. The results demonstrate no change in morphine antinociception and pharmacokinetics with age, and suggest that blood-brain barrier permeability and reception sensitivity to morphine are not altered in aged rats. Accumulation of M3G in plasma of aged rats is probably due to diminished renal clearance of M3G in addition to a reduction in the biliary excretion of M3G. The heightened sensitivity of the aged rats to M6G is probably due to the observed altered kinetics of M6G rather than a pharmacodynamic change.