Mechanism of hematocrit increase induced by the combined administration of morphine and Adriamycin: Role of histamine release

The mechanism by which morphine interacts with Adriamycin to increase hematocrit has been investigated in mice. Treatment with Adriamycin (12.8 mg/kg, iv) or morphine (20 mg/kg, sc) resulted in slight increases in hematocrit 30 min postdose, while animals given sc morphine 30 min prior to iv Adriamycin exhibited significant increases in hematocrit as early as 1 min post-Adriamycin. The hematocrit increase reached maximal levels 12 min post-Adriamycin and returned to basal values 4 hr postdose. Splenectomizing animals prior to morphine and Adriamycin treatment had no effect on the drug-induced hematocrit increase. This indicates that red cell release from splenic contracture is not the mechanism for the hematocrit increase. Measurement of plasma histamine levels following drug treatment demonstrated a marked and rapid rise in plasma histamine levels reaching maximal values 1 min post-Adriamycin. Adriamycin alone triggered this release; however, morphine pretreatment resulted in a higher maximum and more prolonged elevation of plasma histamine levels. Treatment with pyrilamine (3.1-50 mg/kg, ip) prior to morphine and Adriamycin administration partially reversed drug-induced hematocrit increase and protected against resultant lethality. Cimetidine (50-200 mg/kg, ip) treatment was not effective. The temporal relationship between hematocrit and histamine increases suggests a cause/effect relationship between released histamine and hematocrit elevation. Protection by pyrilamine and not cimetidine further supports this cause/effect relationship and indicates the effects is mediated via histamine type 1 receptors.     

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Pretreatment with a single moderate dose of morphine (e.g. 5.6-10 mg/kg) 4-24 hr prior to challenge with an opioid antagonist such as naloxone results in reliable expression of behaviors that resemble aversive or emotional consequences of withdrawal from chronic opioid exposure, including suppression of operant responding, elevations in brain reward thresholds, and conditioned place aversion. Repeated daily or weekly treatment with these same morphine doses results in a progressive increase in naloxone potency to elicit these withdrawal signs. The current study sought to determine whether increased anxiety-like behavior during withdrawal from chronic opioid dependence is also seen after acute morphine exposure, and progresses with repeated intermittent treatment. Male Wistar rats were handled and injected with either vehicle or morphine for 4 consecutive days. Three injection regimens were employed: Morphine Naive (4 vehicle injections), Acute Morphine (3 vehicle injections, 4th injection 5.6 or 10 mg/kg morphine), or Repeat Morphine (all 4 injections with 5.6 or 10 mg/kg morphine). Acute pretreatment with 5.6 mg/kg or 10 mg/kg morphine resulted in time-dependent increases in exploration of the open arms of the plus maze in naloxone-naive rats when tested at 2, 4 or 8 hr after the final pretreatment injection, with the effects at the higher dose appearing later (4 hr) than after the lower dose (2 hr). This pattern of results, in combination with a separate study which confirmed a significant anxiolytic-like effect of a low dose of morphine (0.56 mg/kg) administered 15 min prior to test, suggested that low residual morphine levels remaining in plasma at 2-4 hr after 5.6 and 10 mg/kg morphine may be sufficient to elicit anxiolytic-like effects. Repeat treatment with either dose of morphine resulted in a further increase in the magnitude and duration of this anxiolytic-like effect. These effects had dissipated by 8 hr post-morphine, and therefore precipitation of withdrawal by one of several doses of naloxone (0.10-3.3 mg/kg) was assessed in separate cohorts of rats 8 hr after the final pretreatment under Morphine Naïve, Acute Morphine, or Repeat Morphine conditions. Naloxone resulted in a significant dose-dependent expression of anxiety-like behavior with no effects on general activity after Acute Morphine pretreatment at either 5.6 or 10 mg/kg morphine. A further significant shift in naloxone potency was observed after Repeat Morphine pretreatment at the 10 mg/kg but not the 5.6 mg/kg dose. Thus, anxiety-like behavior is a prominent feature of the negative emotional consequences of naloxone-precipitated withdrawal from acute opioid dependence.     

Interaction of clonidine and morphine with lidocaine in mice and rats

Morphine and clonidine both elevated plasma levels of lidocaine to the same extent in mice while slowing lidocaine metabolism to deethylated products. The effects of clonidine on lidocaine disposition were reversed by yohimbine. Mice given morphine, 20 mg/kg sc, or clonidine, 0.2 mg/kg sc, had similar, 30-50%, elevation of plasma lidocaine levels at 15 min after lidocaine, 15 mg/kg iv, when compared to saline-treated animals. Despite similarity of effect on plasma lidocaine, mice treated with morphine were much more susceptible to lethal effects of lidocaine than were mice given clonidine. At iv doses of 22 mg/kg or higher, lidocaine caused death in nearly all morphine-treated mice, while even 32 mg/kg lidocaine caused only 11% mortality after saline or clonidine. Clonidine, 0.5 mg/kg sc, and morphine, 20 mg/kg sc, both raised plasma lidocaine levels in rats, but only morphine depressed respiration, causing hypoxia, hypercapnia, and acidosis and increasing lidocaine lethality. These data suggest that potentiation of lidocaine toxicity by morphine is due primarily to changes in blood gases rather than to elevation in lidocaine levels.     

Morphine effects on gentamicin disposition and toxicity in mice

Morphine has been shown to reduce renal and hepatic clearance of several xenobiotics in rodents. After iv administration of gentamicin, 10 to 30 mg/kg, its plasma levels were elevated in mice given morphine, 20 mg/kg sc. Plasma clearance of gentamicin was nearly halved by morphine, due primarily to lowering of the elimination constant of gentamicin from 0.03 to 0.02 min-1 (p less than 0.01). Morphine also significantly reduced urine levels of gentamicin and urine volume. In mice given naloxone, 2 mg/kg sc, morphine did not significantly raise plasma levels of gentamicin nor reduce its elimination into urine. Mice were made tolerant by morphine administration for 9 days at ascending doses to 100 mg/kg twice daily. An acute challenge with morphine, 20 mg/kg, was less effective in raising plasma levels of gentamicin or lowering its urinary elimination in tolerant mice than after chronic saline treatment. Partial tolerance to acutely administered morphine and reversal of morphine effects by naloxone suggest opioid receptor-mediated reduction of glomerular filtration by morphine in mice. Despite marked elevation of plasma gentamicin levels in morphine-treated mice, narcotic administration did not significantly increase the acute toxicity of a single dose of gentamicin. LD50 of acutely administered iv gentamicin was 51.6 mg/kg after saline and 45.3 mg/kg after treatment with morphine, 20 mg/kg sc. However, this dose of morphine enhanced the lethality of intravenously infused gentamicin. Morphine administration significantly reduced the dose of infused gentamicin needed to achieve the critical lethal plasma level.     

Morphine-ethanol interaction on body temperature.

1. The interaction between ethanol and morphine on core temperature was investigated in Swiss Webster mice. 2. Morphine (2.5-30 mg/kg) and ethanol (0.5-3.0 mg/g) administered individually resulted in a dose dependent decrease in body temperature. 3. When both drugs were injected simultaneously, body temperature decreased less than it would be expected to if the effects were additive. 4. Naloxone antagonized the hypothermic effect of morphine, but the hypothermic effect of ethanol and that of the combination of morphine plus ethanol was only reversed with high doses of naloxone (10 mg/kg). 5. Individual morphine and ethanol plasma levels were not significantly altered by their concomitant administration. 6. Binding of tritiated naloxone to opiate receptors in mouse brain membrane preparations was unchanged by pretreatment with ethanol (0.5 and 2 mg/g). 7. The interaction between morphine and ethanol was found to be less than additive and not related to pharmacokinetic changes of either drug.     

吗啡抑制呼吸与呼吸中枢胆碱能的关系

本文以兔呼吸频率、通气量和血气为指标,观察到icv匹鲁卡品和促进Ach释放的4-氨基吡啶能拮抗吗啡的呼吸抑制作用。吗啡在抑制呼吸的同时,降低延髓和脑桥Ach含量,呼吸频率抑制率与Ach含量下降率间具有正相关。表明吗啡抑制呼吸与低位脑干Ach含量下降、因而减少Ach释放有关。     

Effects of morphine on methotrexate disposition in mice

1. Morphine has been shown to slow the renal excretion of other drugs. The present study in mice evaluated the effects of morphine on the disposition of methotrexate (MTX), an antimetabolite eliminated by the kidneys. 2. Mice were injected with morphine (20 mg/kg) or saline s.c. After 30 min, 20-80 mg/kg MTX was injected i.v. Blood and urine samples were assayed for MTX by HPLC. 3. Morphine reduced plasma clearance (CL) of MTX from 0.147 +/- 0.015 to 0.061 +/- 0.009 mL/min per g bodyweight (P < 0.01). The area under the plasma concentration-time curve (AUC(0- infinity )) was raised by morphine from 151 +/- 18 to 369 +/- 36 micro g.mL per min (P < 0.01). Without morphine administration, 22-27% of an MTX dose was excreted into the urine in 30 min. The corresponding fractions excreted into the urine after morphine were reduced to 15-18% (P < 0.01). 4. Plasma levels of MTX administered intravenously to mice are elevated by the concomitant administration of morphine, which reduces renal elimination of MTX.     

Involvement of Opioid Receptors in Shaking Behaviour Induced by Paraquat in Rats

Paraquat (30-70 mg/kg intraperitoneally) caused typical shaking behaviour in rats in a dose-dependent manner. Myoclonus also appeared after the shaking behaviour in several rats treated with the highest dose of paraquat. Morphine (5 mg/kg intraperitoneally, 30 min. before paraquat) significantly reduced the frequency of shaking behaviour. The alleviation by morphine disappeared when naloxone (1.5 mg/kg intraperitoneally 15 min. after morphine) was coadministered. Although there was no histological change in brain slices of paraquat-treated rats (70 mg/kg intraperitoneally), the fluorescein uptake into brain was increased by the treatment. Morphine prevented the increase of fluorescein uptake, but naloxone failed to antagonize this effect. On the other hand, intracerebroventricularly administered paraquat (25.7 μg/rat) caused tremor in all rats, but not shaking behaviour nor myoclonus. These findings suggest that paraquat administered systemically as well as centrally may be toxic to the brain. Although the actions of paraquat on the brain seem to be complicated, opioid receptors may play a role in the actions.     

HYPOTHERMIA ENHANCES THE EFFECTS OF MORPHINE ON HORMONAL AND HISTAMINE RELEASE

1. The effects of intravenous (i.v.) morphine on adrenocorticotrophic hormone (ACTH), beta-endorphin (beta-END), total catecholamines (CA) and histamine (HIS) plasma concentrations, were determined in anaesthetized dogs at 30 degrees C and 37 degrees C. 2. Hypothermia initially increased CA levels by 29%, but the values returned to baseline after 2 h. Morphine (1 mg/kg, i.v.) produced a significant decrease in CA both at 37 degrees C and 30 degrees C (34% and 54%, respectively). Subsequent administration of naloxone (1 mg/kg, i.v.) significantly increased CA levels in both groups. 3. Hypothermia per se had no effect on ACTH, beta-END, and HIS concentrations. Morphine produced a significant increase in pituitary hormones and HIS, in hypothermic but not in normothermic animals. Morphine concentrations were significantly higher at 30 degrees C during the first 45 min. 4. The results suggest that the effects of morphine on hormonal and histamine release observed at 30 degrees C are concentration-dependent and related to changes in morphine pharmacokinetics.     

EFFECTS OF MORPHINE ON BRAIN HISTAMINE, ANTINOCICEPTION AND ACTIVITY IN MICE

1. The effect of morphine on the histamine content of the mouse brain has been investigated. The changes in the brain histamine level have been related to morphine-induced analgesia and morphine-induced changes in locomotor activity. 2. With doses of morphine between 1 and 5 mg/kg there was a significant increase in histamine levels. The time required to produce a maximal rise in the brain histamine level with 5 mg/kg of morphine was 15 min. 3. There was a significant decrease in brain histamine levels with doses of morphine between 7.5 and 100 mg/kg. The time at which the greatest decrease was produced with 50 mg/kg was 30 min. 4. The time course of the alteration of brain histamine by morphine did not correlate with its antinociceptive activity. Both the 5 and 50 mg/kg doses of morphine produced analgesia in mice whereas brain histamine levels were increased and decreased, respectively. 5. Pretreating mice with compounds which modify histaminergic function did not modify the antinociceptive action of morphine. 6. Morphine produced a biphasic effect on locomotor activity when the dose was increased from 0.5 through to 100 mg/kg. Doses up to 2.5 mg/kg caused a reduction of activity and doses above this produced significant increases. 7. There appears to be an inverse relationship between the morphine-induced changes of brain histamine and the morphine-induced changes in locomotor activity.     

Acute morphine effects on regional brain amines, growth hormone and corticosterone.

Morphine sulfate was injected in doses of 5, 10 and 20 mg/kg i.p. to male rats at 3:00 pm. At 4:00 pm, the rats were decapitated and norepinephrine, dopamine and serotonin levels were measured in seven brain regions (cortex, striatum septum, amygdala, hypothalamus, midbrain and pons). Growth hormone and corticosterone levels were assayed from plasma. Saline-injected animals served as controls. The only significant change in brain amine level was an increase in striatal dopamine which occurred after 5 mg/kg morphine. 20 mg/kg caused an increase in plasma corticosterone; lower doses were ineffective. The dose for maximum growth hormone release was 10 mg/kg, although all three doses were effective. It was not possible to relate changes in brain amine levels with these hormonal responses to acute morphine administration.     

Metyrapone and mifepristone reverse recognition memory loss induced by spontaneous morphine withdrawal in mice

Morphine withdrawal leads to an increase in corticosterone concentration in plasma, and cognitive deficits are found after withdrawal. Evidence indicates that glucocorticoid hormones affect memory. The aim of the current study was to evaluate the effects of metyrapone and mifepristone on memory deficit following spontaneous morphine withdrawal. Memory was tested by using the object recognition task. The novel object recognition task was carried out in a square wooden open-field apparatus using objects. The test was comprised of three sections: habituation for 15 min., first trial for 12 min. and test trial for 5 min. In this learning paradigm, the difference in exploration between a previously seen object and a novel object is taken as an index of memory performance (recognition index - RI). Male mice were made dependent by increasing doses of morphine (30-90 mg/kg) subcutaneously twice daily for 3 days. RI was assessed 4 hr after the last dose of morphine on the third day. Mifepristone (50 and 100 mg/kg) and metyrapone (12.5 and 25 mg/kg) were used subcutaneously before the first trial and effects were compared to control values. Metyrapone (25 mg/kg) and mifepristone (50 mg/kg) improved RI to 34.8 +/- 10.8% and 25.4 +/- 11.7%, respectively, which are significantly different from control values (RI = -14.8 +/- 10.7%, P < 0.05). These results show that increased glucocorticoid concentration may be involved in memory deficit caused by morphine withdrawal. Metyrapone by inhibiting glucocorticoid formation, and mifepristone by inhibiting glucocorticoid receptors may be useful for preventing memory deficit following morphine withdrawal.     

Effects of quinidine on antinociception and pharmacokinetics of morphine in rats

Aim The aim of this study was to investigate the effect of quinidine, a P‐glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of morphine in rats. Methods Rats were given morphine (30 mg/kg p.o. or 30 mg/kg over 10 min i.v.) 30 min after pretreatment with quinidine (30 mg/kg p.o.). Antinociceptive effects were determined using the tail immersion test. Concentrations of morphine in plasma and brain were also determined. Key findings The antinociception of morphine was significantly enhanced by oral administration of quinidine, with a 3.1‐fold greater area under the effect–time curve than that in vehicle‐treated rats. Morphine concentrations in plasma and brain were significantly increased by quinidine. The area under the plasma concentration–time curve after oral or intravenous administration of morphine was increased 5.2‐ and 1.7‐fold, respectively, in quinidine‐pretreated rats compared with vehicle‐pretreated rats. Quinidine caused a 40% decrease in the total clearance of morphine and increased the concentration of morphine in the brain, although the brain‐to‐plasma concentration ratio was not changed. Conclusions Oral administration of quinidine increases the absorption of morphine from the gastrointestinal tract and subsequently enhances the concentration in the brain and its antinociceptive effect. Enhanced intestinal absorption of morphine may be due largely to inhibition of intestinal P‐glycoprotein by quinidine.     

Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.     

Acute effects of morphine and chlorpromazine on the acquisition of shuttle box conditioned avoidance response

Morphine sulfate, 0.25–24.0 mg/kg, or chlorpromazine hydrochloride, 0.0625–4.0 mg/kg, were administered subcutaneously to naive rats 30 min prior to the start of massed-trials conditioned avoidance response (CAR) testing. The graded doses of both drugs were applied in each of three CAR task difficulty levels created by manipulation of the duration of conditioned and unconditioned stimuli, intertrial interval and shock intensity. Chlorpromazine, in a dose-related manner, caused a decrement in CAR acquisition in all tasks. Morphine, in comparison, produced a biphasic dose response. For a given task difficulty, low doses of morphine enhanced acquisition, whereas higher doses inhibited acquisition. With increasing task difficulty, relatively larger doses of morphine were required to inhibit or facilitate acquisition of CAR. These results emphasize the need to consider not only drug dosage levels, but also the interaction of task difficulty in the application of drugs in learning paradigms.     

Influence of stress in the effects of morphine on pituitary-adrenocortical activity in the guinea-pig

1. Modifications by stress of the effects of morphine on pituitary-adrenocortical activity were examined in the guinea-pig at different lengths of time. 2. An increase in plasma cortisol but not in beta-endorphin levels was obtained in guinea-pigs stressed for 60 min. 3. Morphine (50 mg kg i.p.) enhanced beta-endorphin and cortisol levels 5 min after injection and decreased beta-endorphin concentration 30 and 90 min after its administration. 4. In stressed guinea-pigs plasma beta-endorphin levels were reduced 5 min after morphine injection. 5. These results indicate that stress can alter the effects of morphine on pituitary-adrenal activity in the guinea-pig and that the type of modification may be dependent on the time of the sampling.     

Effects of levo-alpha-acetylmethadol (LAAM) on morphine self-administration in the rat

Rats bearing cerebrocortical electrodes for recording the electroencephalogram (EEG) were rendered tolerant to and physically dependent on morphine and subsequently trained to self-administer morphine (10 mg/kg/injection) through a chronic intravenous cannula. Morphine was available for selfadministration 24 h/day. Once morphine intake had stabilized (10–12 injections/day), levo-alpha-acetylmethadol (LAAM) was administered noncontingently via a chronic intragastric (IG) cannula as a single daily dose of either 1 or 4 mg/kg. These morphine self-administering rats were maintained on daily LAAM treatment for 12 consecutive days. Analysis of the patterns of lever pressing, morphine self-injections, and sleepawake behavior revealed that daily IG administration of LAAM effectively suppressed morphine self-administration. The 1 mg/kg dose of LAAM reduced morphine intake by 30%–50%, while 4 mg/kg produced an 80%–90% decrease. The reduction in morphine self-administration occurred in the absence of overt signs of narcotic withdrawal, behavioral toxicity, or disruption of sleep-awake behavior in these rats. Termination of LAAM maintenance resulted in a gradual return of lever pressing and morphine intake to pre-LAAM levels.Preliminary report of this study appeared in The Pharmacologist 21, 226 (1979)     

Pharmacokinetics of epidural morphine in man

Summary Cerebrospinal fluid (CSF) and plasma morphine concentrations were determined in 5 patients after epidural administration of 6 mg morphine; plasma samples were collected frequently during the initial 6 h and 6–7 CSF samples were obtained from each patient over a 24 h period. Morphine was analysed using gas chromatography and electron capture detection. Individual morphine concentration-time curves were plotted for plasma and CSF and various pharmacokinetic variables were calculated. Plasma morphine concentrations after epidural injection were similar to those found after intramuscular administration; C_max (66±8 mg/ml: mean±SEM) appeared within 12±3 min, and the terminal elimination half-life in plasma was 213±24 min. In CSF, morphine reached a peak (1575±359 ng/ml) after 135±40 min. The terminal elimination half-life for morphine in CSF was 239±10 min. The CSF bioavailability of morphine after epidural administration was calculated to be 1.9±0.5%.The study showed that epidural administration of morphine resulted in CSF concentrations many times higher than those in plasma, but still only 2% of the dose administered was available to the CSF compartment. Morphine was eliminated with similar speed from CSF and plasma.     

Carbamazepine potentiates morphine analgesia on postoperative pain in morphine-dependent rats

Postoperative pain and its control remain one of the most important issues in the field of surgery and health care systems. Morphine is a potent and effective analgesic, but substance abuse patients can manifest cross-tolerance to it, making it difficult to satisfy their analgesic/anesthetic requirements. As carbamazepine has shown antinociceptive properties in a variety of experimental and clinical settings, in the present study, we evaluated its potential antiallodynic effects on postoperative pain in na?ve and morphine-dependent rats. Male rats were assigned to morphine-dependent and na?ve groups and received intraperitoneally drug vehicles as control group, 3mg/kg morphine, 5, 10 or 15 mg/kg carbamazepine or 5mg/kg carbamazepine plus 3mg/kg morphine as a combination therapy 2 and 24h after surgery. Morphine-dependency was induced with multiple doses of morphine administered i.p. and plantar incision was made on the hind paw to simulate the postoperative pain. Paw withdrawal threshold (PWT) was obtained by von Frey filaments every 30 min after drug injection for up to 180 min. Morphine at 3mg/kg exerted antiallodynic effects in na?ve rats and a decreased antinociception was observed in morphine-dependent rats. In contrast, 5mg/kg carbamazepine did not significantly alter PWT in naives but it was effective in dependent rats. 10 and 15 mg/kg carbamazepine attenuated allodynia following surgery in both groups. Co-administration of 5mg/kg carbamazepine with 3mg/kg morphine produced higher analgesia in morphine-dependent incised rats and prolonged antinociception as compared to morphine alone (P<0.05). Thus carbamazepine may potentiate the analgesic effect of chronically administered morphine on postoperative pain model in morphine-dependent rats.     

Extrahepatic glucuronidation of morphine in the dog

The pharmacokinetic disposition of morphine was studied in sham-operated dogs, dogs with hepatic devascularization, and dogs with bile duct and ureter ligation after iv administration of 1 mg/kg of morphine. In sham-operated dogs, morphine is rapidly distributed and eliminated, with a terminal half-life of 65 +/- 30 min. Morphine glucuronide appeared in plasma within 5 min and rose rapidly to levels an order of magnitude higher than morphine levels, before both declined in parallel. In hepatic devascularized dogs, there was a marked delay in morphine elimination due to a 47% reduction in clearance. The appearance of morphine glucuronide in plasma was not delayed, but the AUC of morphine glucuronide was reduced by 56% compared to control for the first 180 min. In bile duct- and ureter-ligated dogs, elimination of morphine was increased and morphine glucuronide elimination from plasma was decreased, suggesting that glucuronide normally excreted in bile is hydrolyzed back to the parent compound and reabsorbed in sham-operated control animals. In conclusion, morphine was glucuronidated by both hepatic and extrahepatic glucuronyltransferases to an approximately equal extent in the dog.