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E Bodd

Publications and source records attributed to E Bodd.

31 records · Page 2Linked to original sources
PubMed1986

Mechanisms behind the inhibitory effect of ethanol on the conjugation of morphine in rat hepatocytes.

Liver microsomes were isolated by calcium aggregation, and isolated hepatocytes from male Wistar rats were prepared according to a two-step Ca++-free collagenase perfusion method. With the hepatocytes maximal inhibition of glucuronidation (about 40%) was reached at 10 mM ethanol after incubation at 37 degrees C for 60 min. UDP-glucuronic acid concentration and energy charge in the hepatocytes also did decrease maximally (about 90 and 50%, respectively) and the amount of UDP-glucose was tripled in the presence of 10 mM and higher concentrations of ethanol. The alcohol dehydrogenase inhibitor 4-methylpyrazole abolished ethanol-induced inhibition of morphine glucuronidation in the hepatocytes. Acetaldehyde (250-50 microM) and the pH decrease induced by ethanol did not reduce morphine-3-glucuronide formation by the cells. Cellular uptake of morphine and excretion of morphine metabolites were similar in the absence and presence of ethanol. Ethanol (60 mM) did not affect the glucuronidation of morphine (1.7 mM added) during a 30-min incubation at 37 degrees C with the microsomes (UDP-glucuronic acid, 5 mM). When the concentration of UDP-glucuronic acid in the microsomes was lowered from 1 to 0.1 mM, the decrease in morphine-3-glucuronide formation was similar to that observed in cells. The data indicate that the inhibition by ethanol of morphine glucuronidation was due to decreased levels of UDP-glucuronic acid. The mechanism is likely to be inhibition of UDP-glucose dehydrogenase activity by ethanol from increased intracellular NADH/NAD ratio accompanying ethanol oxidation.

Animals↗
PubMed1986

Ethanol inhibition of codeine and morphine metabolism in isolated rat hepatocytes.

Suspensions of isolated hepatocytes from male Wistar rats were prepared according to a two step Ca++-free collagenase perfusion method. Codeine, morphine or norcodeine were incubated with hepatocytes at 37 degrees C for up to 90 min in the absence and presence of ethanol. The elimination rate constant (Kel) of codeine and morphine was reduced with approximately one-third and one-fourth, respectively, in the presence of 60 mM ethanol, whereas the presence of ethanol did not alter the Kel of norcodeine significantly. The inhibition of codeine metabolism was dose-dependent, extending from approximately 15% at 10 mM ethanol to 40 to 50% at 100 mM. A 3-fold increase in the ratio of morphine concentration (formed from codeine) to the amount of codeine metabolized was observed in the presence of ethanol as compared to control cells. The mean morphine concentration was 170% higher in the ethanol-treated suspensions than in the controls. The ratio of norcodeine concentration to codeine metabolized was unchanged. The inhibition of morphine metabolism was accompanied by a similar reduction of morphine-3-glucuronide formation. The accumulation of morphine observed in the cell medium in the presence of ethanol might be due to inhibition of other metabolic pathways from codeine, thus shunting to morphine formation, combined with the inhibitory effect of ethanol on morphine metabolism per se.

Animals↗
PubMed1985

Lack of evidence of increased lethality due to propoxyphene overdose in the presence of ethanol in male Wistar rats.

The primary purpose of the present investigation was to evaluate if the presence of ethanol increased lethality induced by propoxyphene. A secondary aim was to study the effect of naloxone on propoxyphene lethality alone, and on the concomitant administration of propoxyphene and ethanol. Male Wistar rats (210-330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats, received either of the following drug treatments: Propoxyphene, ethanol + propoxyphene, naloxone + propoxyphene, and naloxone + ethanol + propoxyphene respectively. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. Some animals died despite naloxone administration, possibly due to a nonopioid cardiotoxic effect of propoxyphene or its metabolite. An increase in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain, and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. In the animals which died, the highest P/N ratio was observed in brain tissue and the lowest in heart muscle. Despite the pharmacokinetic data obtained in this investigation indicating impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene-induced lethality.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Ethanol interaction with propoxyphene and norpropoxyphene metabolism in isolated rat hepatocytes.

Suspensions of isolated rat hepatocytes (approximately 7.5 X 10(5) cells/ml) metabolized added propoxyphene and norpropoxyphene rapidly. At 2 microM, the metabolism of both drugs obeyed first-order elimination kinetics. Increasing propoxyphene concentrations (1, 2, 4 and 8 microM) gradually increased the medium concentrations of norpropoxyphene. The total propoxyphene metabolism was the same at 4 and 8 microM. The effect of ethanol (10 and 60 mM) on propoxyphene (2 microM) and norpropoxyphene (2 microM) metabolism in suspensions of isolated rat hepatocytes was studied. The half-lives of propoxyphene were 7.1 +/- 5.5 min in absence and 6.7 +/- 2.8 min in presence of 10 mM ethanol, but increased to 10.7 +/- 5.8 min in presence of 60 mM ethanol (p less than 0.05). The half-lives of added norpropoxyphene increased from 17.9 +/- 4.1 min to 26.0 +/- 7.3 min at 10 mM ethanol (p less than 0.05) and 29.3 +/- 5.9 min at 60 mM ethanol (p less than 0.05). Ethanol (60 mM) reduced the elimination rate constant of propoxyphene and norpropoxyphene by 31 +/- 25% and 38 +/- 15%, respectively.

Animals↗
PubMedDate not supplied

Interaction of ethanol with codeine metabolism in rat hepatocytes: a multicompartmental model.

A multicompartmental pharmacokinetic model is presented, which based upon data from a previous study, describes the effects of ethanol (60 mM) on the metabolism of codeine (10 microM) in isolated rat hepatocytes. According to this model, about one third of codeine metabolized was transformed to morphine (13%) and norcodeine (18%), and two-thirds to unknown metabolites in the absence of ethanol. In the presence of ethanol, the apparent first order fractional rate of total codeine metabolism was reduced by 66% (0.0783 vs 0.0271 min-1). There was no alteration in the portion of codeine metabolized to norcodeine, but there was a 44% decrease in the fraction transformed to unknown metabolites and a tripling in the portion transformed to morphine. The fractional rate of codeine O-demethylation to morphine was apparently not sensitive to ethanol. In the absence of ethanol, about two-thirds of morphine was metabolized to morphine-3-glucuronide and the other third to unidentified metabolites. Only the glucuronidation process seemed to be inhibited by ethanol. The fractional rate of further metabolism of norcodeine to normorphine was similar in the absence or presence of ethanol. In conclusion ethanol co-incubation with codeine resulted in an inhibition of codeine conversion to unknown metabolites and norcodeine, and with morphine to morphine-3-glucuronide, but no inhibition in morphine production.

Animals↗
PubMedDate not supplied

Ethanol does not increase lethality due to propoxyphene in rats.

Male Wistar rats (210-330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats received either of the following drug treatments: Propoxyphene; ethanol + propoxyphene; naloxone + propoxyphene; and naloxone + ethanol + propoxyphene. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene as compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. A rise in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. Although these pharmacokinetic data indicate impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene induced lethality. This is also contrary to suggestions from previous studies. Our results demonstrate that at least in one species and at one dose ratio (ethanol/propoxyphene) ethanol might reduce the lethality caused by propoxyphene alone. This suggests antagonism between the two drugs, probably in the central nervous system.

Animals↗