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1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine‐6‐glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine‐6‐glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/‐ 0.31 h (mean +/‐ s.d.) and for codeine‐6‐glucuronide it was 1.28 +/‐ 0.49 h. The plasma AUC of codeine‐ 6‐glucuronide was 15.8 +/‐ 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/‐ 1.1 times higher than that in plasma. The elimination half‐life of codeine was 3.2 +/‐ 0.3 h and that of codeine‐6‐glucuronide was 3.2 +/‐ 0.9 h. 3. The renal clearance of codeine was 183 +/‐ 59 ml min‐1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine‐6‐glucuronide was 55 +/‐ 21 ml min‐1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine‐6‐glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine‐6‐glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/‐ 11.4% of the dose was recovered in urine, of which 59.8 +/‐ 10.3% was codeine‐6‐glucuronide, 7.1 +/‐ 1.1% was total morphine, 6.9 +/‐ 2.1% was total norcodeine and 11.8 +/‐ 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/‐ 31 ml min‐1 in the seven extensive metabolisers and 8 ml min‐1 in the poor metaboliser; to norcodeine the values were 103 +/‐ 33 ml min‐1 and 90 ml min‐1; to codeine‐6‐ glucuronide the values were 914 +/‐ 129 ml min‐1 and 971 ml min‐1; and intrinsic clearance was 1568 +/‐ 103 ml min‐1 and 1450 ml min‐1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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1. The aims of the present study were to determine the relationship between the antinociceptive effect and concentrations of morphine and morphine-6 beta-glucuronide (M6G) in plasma and in the brain. 2. Morphine (14.0 and 28.0 mumol/kg) or M6G (8.67 and 17.3 mumol/kg) were administered s.c. to male Hooded-Wistar rats. The antinociceptive effect was measured by the thermal tail-flick method at various times up to 2 h and concentrations of morphine, morphine-3 beta-glucuronide (M3G) and M6G in plasma and in the brain were determined. 3. With a two-fold increment in morphine dose, the areas under the antinociceptive effect-, plasma morphine concentration- and brain morphine concentration-time curves increased by 1.9-, 2.3- and 2.3-fold, respectively. The area under the plasma M3G concentration-time curve increased 2.7-fold. Morphine-6 beta-glucuronide was not detected in any sample. For M6G, doubling of the dose led to a 1.7-fold increase in the area under the curve for plasma-time M6G concentrations but an 8.7-fold increase in the area under the curve for the antinociception-time effect. Concentrations of M6G in the brain were below the limit of quantification. The relationship between antinociceptive effect and plasma morphine or M6G were characterized by counter-clockwise hysteresis loops, probably reflecting a delay in crossing the blood-brain barrier. 4. Morphine-6 beta-glucuronide was approximately equipotent to morphine on the basis of dose, but substantially more potent on the basis of brain concentration.

Dose-response curves were constructed for intrathecal morphine (M), oxymorphone (OM), hydromorphone (HM), diamorphine (DM), 14-hydroxydihydromorphine (OHM), oxycodone (OC), hydrocodone (HC) and fentanyl (F). Intrathecal catheters were placed in 69 rats under halothane/N2O anaesthesia. After recovery, baseline hot plate and tail flick latencies were measured, and a dose of opioid was given. Hot plate and tail flick latencies were assessed at 5, 15, 30, 60, 90, 120 min and then hourly until they returned to within 25% of baseline. Response latencies were converted to per cent of maximum possible effect (% MPE) and the area under the % MPE X time curve was taken as the response. This measure includes information about both potency and duration of action. Each rat received 3 opioids and saline at intervals of 2-3 days. On a fifth occasion, the animal's first treatment was repeated. Each opioid was studied over an 8-fold dose range. Results of both hot plate and tail flick were best described by a model including log(dose), a component due to development of tolerance over the 5 experimental days, and an among-rat variation term. In the hot plate test, doses equieffective in producing a response (AUC) over the dose range studied were in the order OHM less than OM less than HM less than M less than F less than DM less than HC less than OC. Slopes of the log(dose)-response curves were similar for all drugs except OHM, which had a steeper slope. A model is proposed in which hot plate and tail flick latencies are prolonged while CSF concentrations of a drug are above its minimum effective concentration, and drug is cleared from the CSF by a first-order process, possibly uptake into the spinal cord and removal via the blood. This model predicts that log(dose)-response curves will be linear, as was observed, with slopes inversely proportional to the rate constant for clearance from CSF. According to this model the steeper slope of the OHM log(dose)-response may be interpreted as indicating slower clearance from CSF. OHM has the lowest octanol/pH 7.4 buffer distribution coefficient (0.34) of all opioids studied, possibly leading to a lower rate of uptake into the spinal cord.