Extrahepatic metabolism of morphine occurs in humans.

The pharmacokinetics of morphine was studied in six patients in whom a radiologic localization of an insulinoma was to be performed under general anesthesia. Sampling was done in the peripheral artery, the mesenteric vein in five of the six patients, the hepatic vein, and the peripheral vein, as well as in urine. Hepatic blood flow was estimated by an indocyanine green infusion technique at the end of the radiologic procedure. Morphine terminal half-life was 92 +/- 9 minutes, total body clearance was 1260 ml.min-1, and the hepatic extraction ratio was 0.65 +/- 0.11. No concentration gradient was observed between the artery and the superior mesenteric vein, showing that no gut wall metabolism of morphine occurred. The total body clearance exceeded the hepatic clearance by 38%. It was concluded that the extrahepatic extraintestinal clearance of morphine probably occurred through the kidney.

Morphine pharmacokinetics and pain assessment after intracerebroventricular administration in patients with terminal cancer.

Morphine pharmacokinetics and pain relief were evaluated after intracerebroventricular administration of morphine (0.4 +/- 0.11 mg) in seven patients with cancer suffering from intractable pain. Ventricular cerebrospinal fluid (CSF), lumbar CSF, and plasma morphine concentrations were analyzed by a specific morphine radioimmunoassay. A two-compartment model was sufficient to describe the kinetics of morphine in ventricular CSF. Morphine diffuses to the lumbar level, and the mean maximum concentration was 192 +/- 105 ng/ml at 4.5 +/- 1.3 hours. Ventricular and lumbar CSF morphine kinetics showed a similar decline during the elimination phase, with terminal half-lives of 3.8 +/- 0.6 hours and 4.2 +/- 1.6 hours, respectively. Pain relief was evaluated by a visual analog scale: the test showed a rapid onset of analgesia (less than 10 minutes). Analgesic effectiveness reached a maximum between 6 and 10 hours. The relationship between pharmacologic effect and morphine concentrations in ventricular CSF resulted in an anticlockwise hysteresis curve. The presence of morphine in lumbar CSF suggested an additive spinal action of morphine, which probably plays a role in the duration of analgesia.

Levels of morphine and metabolites in CSF during respiratory depression after intraventricular morphine injection.

We report a case of respiratory depression after intracerebroventricular morphine administration of a dose inadvertently 10 times greater than the typical daily dose. At the time of the respiratory dysfunction, the concentrations of morphine and its metabolites in cerebrospinal fluid (CSF) and plasma samples were determined. On comparison of these results with previous clinical studies in which there was no respiratory depression, no relationship was found between the occurrence of respiratory depression and the concentration of morphine or its metabolites in the CSF. The occurrence and characteristics of respiratory depression may be related to the concentrations of morphine and its metabolites in bulbar tissue.

Elevated concentrations of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability.

1 This study was done to find out how morphine 6-beta-D-glucuronide (M6G) induces more potent central analgesia than morphine, despite its poor blood-brain barrier (BBB) permeability. The brain uptake and disposition of these compounds were investigated in plasma and in various brain compartments: extracellular fluid (ECF), intracellular space (ICS) and cerebrospinal fluid (CSF). 2 Morphine or M6G was given to rats at 10 mg kg(-1) s.c. Transcortical microdialysis was used to assess their distributions in the brain ECF. Conventional tissue homogenization was used to determine the distribution in the cortex and whole brain. These two procedures were combined to estimate drug distribution in the brain ICS. The blood and CSF pharmacokinetics were also determined. 3 Plasma concentration data for M6G were much higher than those of morphine, with Cmax and AUC 4-5 times more higher, Tmax shorter, and VZf-1 (volume of distribution) and CL f(-1) (clearance) 4-6 times lower. The concentrations of the compounds in various brain compartments also differed: AUC values for M6G were lower than those of morphine in tissue and CSF and higher in brain ECF. AUC values in brain show that morphine levels were four times higher in ICS than in ECF, whereas M6G levels were 125 higher in ECF than in ICS. 4 Morphine entered brain cells, whereas M6G was almost exclusively extracellular. This high extracellular concentration, coupled with extremely slow diffusion into the CSF, indicates that M6G was predominantly trapped in the extracellular fluid and therefore durably available to bind at opioid receptors.

Effect of social isolation on the metabolism of morphine and its passage through the blood-brain barrier and on consumption of sucrose solutions.

RATIONALE: We have previously shown that place preference conditioning to morphine was observed in social mice at the dose of 8 mg/kg, whereas 4 weeks of isolation impairs the place preference conditioning to morphine (8-100 mg/kg). OBJECTIVE: The present study, aimed at explaining this phenomenon, tested three hypotheses: firstly, a reduced sensitivity to reinforcers induced by isolation; secondly, a difference in morphine disposition in isolated and social mice; thirdly, an altered blood-brain barrier transport of morphine in isolated mice. METHODS: In the sucrose experiments, mice had the choice (for 24 h) between a bottle containing tap water and a bottle containing a sucrose solution. Three sucrose concentrations were used: 0.5, 1 and 2% (weight/weight). In the morphine disposition experiments, the plasma levels of morphine and of morphine-3-glucuronide (M3G) were measured for 240 min. The brain concentrations of morphine was measured at 15 and 30 min. The passage of morphine through the blood-brain barrier was measured using a method modified from that of Takasato (1984). RESULTS: The preference for the sucrose solutions was significantly greater in isolated than in social mice for the concentration of 2%. Isolation reduced the plasma levels of morphine and of M3G, but did not alter the brain concentration of morphine. The passage of morphine through the blood-brain barrier was altered by isolation in neither of the eight structures examined. CONCLUSIONS: We conclude that the behavioural effect of isolation observed in the conditioned place preference to morphine may depend on changes both in morphine disposition and in the sensitivity to reinforcers in isolated mice.

Influence of a dietary alpha-linolenic acid deficiency on learning in the Morris water maze and on the effects of morphine.

Female OF1 mice were fed on a diet deficient in alpha-linolenic acid or on a control diet 3 weeks before mating and throughout pregnancy and lactation. Pups fed on the same diet as their mothers were used for experiments. The effects of dietary alpha-linolenic acid deficiency were studied in a model of learning, the Morris water maze, and on the following effects of morphine: increase in locomotor activity, modifications of rectal temperature and analgesia. In the place and in the cue versions of the Morris water maze, learning occurred at the same speed in the two diet groups; however, in the place version of the test, the level of the performance was significantly lower in the deficient mice. The probe trial and the extinction procedure did not show any difference between the two diet groups. The morphine-induced increase in locomotor activity occurred significantly earlier and was greater in the deficient diet group. Morphine induced an early hypothermia followed by a late hyperthermia; the hypothermia was significantly greater and the hyperthermia significantly smaller in the deficient mice. The pain thresholds and the morphine-induced analgesia were unmodified by the dietary deficiency. The plasma levels of morphine were similar in the two diet groups.

Endogenous digitalis-like immunoreactive substances in cord serum characterized by anti-digitoxin and anti-digoxin antibodies. Effect of modulated incubation conditions.

Digoxin-like immunoreactive substances (DLIS) have been extensively described in biological fluids of pregnant women, neonates and renal impaired patients, by the use of several digoxin immunoassays. In this paper a similar interference with anti-digitoxin antibodies is reported by investigating 20 cord sera. By increasing both the time and the temperature of the incubation, the levels of digitalis-like immunoreactive substances may be modulated and decreased to zero. Digitoxin- and digoxin-like immunoreactive substances have been successfully extracted with methanol and concentrated from cord serum. Our data suggest the competitive nature of DTLIS and DLIS interactions with digitalis antibodies. They also show a means of minimizing these interferences in routine digitalis immunoassays.

Morphine and morphine metabolite kinetics in the rat brain as assessed by transcortical microdialysis.

Morphine (M), morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G) were subcutaneously administered at 10 mg/kg in three groups of six awake rats. A transverse microdialysis probe was implanted in the brain cortex and dialysates were collected every 30 minutes for a period of 4 hours. Dialysates were measured by two different opiate radioimmunoassays. Maximum brain opiate concentrations, 41 +/- 10 ng/ml (M), 147 +/- 27 ng/ml (M3G), 177 +/- 43 ng/ml (M6G), were reached at the same Tmax, 0.75 h, and elimination half-lives ranged from 0.99 to 0.81 h for the 3 compounds. Kinetic parameters confirmed that penetration and elimination rates in the extracellular space of the rat brain cortex for the 2 hydrophilic M metabolites were similar to those of M. These results indicate for the first time that, in spite of their structural differences, glucuronide metabolites of M are capable of crossing the blood-brain-barrier (BBB) at the same rate as morphine does, but in higher amount.

Pharmacokinetics of hydroxocobalamin in dogs.

Hydroxocobalamin is a powerful cyanide antidote that prevents sodium nitroprusside-induced cyanide toxicity. The pharmacokinetics of an i.v. bolus of hydroxocobalamin (70 and 140 mg/kg) were studied in conscious dogs (n = 6). Plasma hydroxocobalamin concentrations were measured using derivative spectrophotometry. The pharmacokinetics were compatible with a two-compartment model with a first-order distribution and elimination rate, and pharmacokinetic parameters were not different between the two doses, except for the elimination half-life. At 70 mg/kg, which is the recommended dose in acute cyanide poisoning, the elimination half-life was 7.36 +/- 0.79 h, the volume of distribution was 0.49 +/- 0.10 L/kg, and the total clearance 0.58 +/- 0.11 L/h. At high doses, hydroxocobalamin has a short elimination half-life and a limited volume of distribution that exceeds blood volume. These results could be useful in elaborating guidelines for the administration of hydroxocobalamin, when repetitive bolus and/or continuous infusion is required.

Single- and repeated-dose pharmacokinetics of intramuscular thiocolchicoside in healthy volunteers.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics and the accumulation and stationarity of thiocolchicoside after repeated intramuscular administration. METHOD: The pharmacokinetics of thiocolchicoside were studied in 6 healthy male volunteers after one single dose and repeated intramuscular doses of 4 mg twice a day for seven days. Plasma and urine samples were assayed for thiocolchicoside levels by a radioimmunoassay (RIA) using a cross-reacting colchicine-specific polyclonal antibody. The pharmacokinetic parameters between the first and the last days were compared using Student's t-test. RESULTS: Thiocolchicoside pharmacokinetic parameters, calculated after the single dose using non-compartmental analysis, were in good agreement with those obtained in previous studies. Following the repeated-dose regimen, the terminal half-life was not significantly different (2.7 (0.3) h) from that predicted from a single-dose (2.8 (0.2) h). The accumulation ratio, based on the repeated-dose/single-dose ratio of AUCtau was approximately 1.25. A decrease of CLT/f was found between day 1 (24.1 (5.2) l/h) and day 7 (19.9 (3.4) l/h), suggesting that moderate time-related alterations occur in the pharmacokinetics of thiocolchicoside, which may be due to a change in its CL(NR) (CL(R) was constant) or to the extent of bioavailability, explained by enterohepatic recirculation. CONCLUSION: Serum thiocolchicoside concentrations accumulated to steady-state when the drug was given twice a day for seven days and the pharmacokinetics were modified. But no adjustments of dose or dosing interval were necessary because the accumulation did not lead to marked change in the plasma levels.

Morphine disposition in opiate-intoxicated patients: relevance of nonspecific opiate immunoassays.

The use of routine nonspecific immunoassays to detect or quantitate opiates in biological fluids raises the question of the relevance of such immunoassays in the investigation of opiate overdose disposition. We investigated the plasma disposition of morphine in 13 patients intoxicated by the intravascular (i.v.) (n = 5) or oral routes (n = 8) using both a highly morphine-specific antibody radioimmunoassay (RIA) and a nonspecific morphine RIA. Both RIAs showed a first-order elimination rate after i.v. intoxication (apparent plasma terminal half-life ranged from 2.9 to 4.7 hours for unchanged morphine and from 3.2 to 4.9 hours for total opiates) and a persistent opiate concentration with rebound after oral ingestion, suggesting a slow release of opiates from the gastrointestinal tract, in dealers and bodypackers. Moreover, i.v. and oral kinetic data were similar for the two RIAs, except for the ratio between total and unchanged morphine concentrations. The nonspecific morphine assay gave a threefold to 16-fold higher concentration than the specific morphine assay but with parallel kinetics for all patients. We conclude that the current, routine nonspecific morphine immunoassays could be a valuable analytical tool for investigating opiate toxicokinetics.

Elemental mercury vapour toxicity: treatment and levels in plasma and urine.

1. We report two cases of acute mercury vapour intoxication in humans. The mercury vapour was released from smelting alloys (gold-mercury amalgam). The alloy was apparently contaminated with an unknown amount of mercury. 2. Within half an hour of the incident, the victims began having moderate headache, nausea, lumbar pain and shortness of breath at rest. The patients were treated with BAL (2,3 dimercaptopropanol), followed by DMSA (2,3 dimercaptosuccinic acid). 3. Serial measurements of mercury metal in plasma and in urine were made for ten days. 4. The results suggest that in spite of the treatment, relatively high concentrations of mercury remain in the plasma for a very long time, and this could be explained by the progressive release of mercury from red blood cells and tissues after oxidation. However, BAL and DMSA did not seem to be the most efficient antidotes. They reduce the plasma inorganic mercury uptake at concentrations of < 50 micrograms I-1.

Presence of morphine metabolites in human cerebrospinal fluid after intracerebroventricular administration of morphine.

After intracerebroventricular administration of morphine in four cancer patients, cerebrospinal fluid (CSF) was analyzed by two morphine radioimmunoassays (RIA), liquid chromatography (LC) and radioreceptor assay (RRA) to evaluate the presence of morphine metabolites. Immunoreactive morphine-like substances were detected by differential RIA's. The maximum concentrations of these compounds were achieved 3 hours after drug administration. These concentrations, according to the specificity of the antiserum, represent a mixture of several metabolites in which only morphine 3-glucuronide(M 3-G) and morphine 6-glucuronide (M 6-G) were identified by LC, and M 6-G by LC-RRA. These results confirm that brain is able to metabolize morphine to inactive (M 3-G) or more potent (M 6-G) derivatives.

[Endogenous digitalis-like substances in umbilical cord blood: analytical interference or new hormones?]. / Composés digitaliques endogènes dans le sérum de cordon: interférences analytiques ou nouvelles hormones?

Endogenous substances with a digitalis-like action have been found in the newborn and in women in the first three months of pregnancy. These substances have three properties that are characteristic of cardiotonic heterosides: a positive inotropic effect; inhibition of Na+, K+-ATPase and binding with anti-digoxin antibodies. The result of this last property, when immunological methods are used to calculate the levels of digoxin, is that significant concentrations of "apparent digoxin" seem to be present although neither the mother nor the newborn child have received any digoxin. We describe the existence of concentrations of the "apparent digoxin" found in 37 cord sera using two radioimmunological methods. In the one, the concentrations were 0.88 +/- 0.20 nmol/L, and in the other 0.17 +/- 0.10 nmol/L. These results emphasize the significant differences obtained when the two methods are used for calculating levels (p less than 0.01). There was no significant variation as far as the geographical origin, the sex of the infant and associated therapy carried out at the delivery. The nature of the interference is not yet known. It could be due to natriuretic hormones or steroids. Its existence gives rise to numerous problems: the physiological role, the validity of pharmacokinetic studies and the control of treatment with digoxin in pregnant women and in the newborn.

[Guidelines for prescription of the assay of digitalis glycosides by immunologic methods]. / Règles de prescription du dosage des digitaliques par méthodes immunologiques.

Digoxin, digitoxin and acetyldigitoxin are the most widely prescribed of cardiotonic glycosides. Analytical exploration can be performed by a single assay when only one compound is prescribed or by multiple assays in cases of imprecise prescription or when several glycosides are given concomitantly. In addition, the metabolic transformation of digitoxin into digoxin and the presence of endogenous "digitalis-like compounds" mean that a number of precautions must be taken during prescription. These examples underline the ambiguity of the so-called "digitalinaemia" prescriptions and the need for biologists to be supplied with maximum information by clinicians.

[Analytical exploration of drug addiction]. / Exploration analytique des toxicomanies.

The natural and synthetic substances most frequently leading to drug addiction are described. They include cannabis, opium and cocaine with their respective derivatives. The authors insist on the problems encountered by analytical chemists when they examine urine samples containing these substances, owing to their metabolic degradation and to interferences between lawful and unlawful drugs. The limitations imposed by these problems to an unambiguous interpretation of the results obtained are defined, but they do not throw any doubt on the value of these investigations.