CYP3A5 but not CYP2D6 polymorphism contributes significantly to the variability in dextropropoxyphene disposition.

This study evaluated the effect of CYP2D6, CYP3A4, and CYP3A5 polymorphisms on dextropropoxyphene disposition in healthy subjects. A total of 14 healthy male Chinese subjects received a single oral dose of a combination tablet of 325 mg of paracetamol and 32.5 mg of dextropropoxyphene. Serial blood samples were collected for up to 24 hours to determine plasma concentrations of paracetamol, dextropropoxyphene, and nordextropropoxyphene by liquid chromatography-tandem mass spectroscopy. CYP2D6, CYP3A4, and CYP3A5 genotyping were performed using polymerase chain reaction-based methods. No CYP3A4 mutant alleles were detected in the study subjects. There were no significant differences (P > .05) in dextropropoxyphene and nordextropropoxyphene pharmacokinetics among CYP2D6 genotypes. In contrast, plasma concentrations of dextropropoxyphene were significantly higher (peak plasma concentration, 54.4 ± 25.5 vs 31.0 ± 10.9 ng/mL; area under the plasma concentration-time curve, 260.8 ± 88.1 vs 142.3 ± 42.4 ng x h/mL, both P < .05) and apparent oral clearance value was significantly lower (2.2 ± 0.9 vs 3.6 ± 1.4 L/h/kg, P < .05) in CYP3A5*3/*3 (n = 8) than CYP3A5*1/*3 (n = 5) subjects. Nordextropropoxyphene exposure also tended to be higher in CYP3A5*3/*3 subjects, but the difference was not statistically significant between the 2 groups. One subject who was identified as a CYP3A5*1/*1 carrier exhibited a very high apparent oral clearance value of 12.5 L/h/kg. No significant difference in paracetamol pharmacokinetics was observed among CYP2D6 or CYP3A5 genotypes. These results suggest that CYP3A5 but not CYP2D6 polymorphisms appear to exert a significant influence on dextropropoxyphene disposition.

CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement.

The individual cytochrome P450 isoforms in dextropropoxyphene N-demethylation to nordextropropoxyphene were determined and the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in cytochrome P4502D6 (CYP2D6) extensive (EM) and poor (PM) subjects were characterized. Microsomes from six CYP2D6 extensive metabolizers and one CYP2D6 poor metabolizer were used with isoform specific chemical and antibody inhibitors and expressed recombinant CYP enzymes. Groups of three CYP2D6 EM and PM subjects received a single 65-mg oral dose of dextropropoxyphene, and blood and urine were collected for 168 and 96 h, respectively. Nordextropropoxyphene formation in vitro was not different between the CYP2D6 extensive metabolizers (Km = 179 +/- 74 microM, Cl(int) = 0.41 +/- 0.26 ml mg(-1)h(-1)) and the PM subject (K = 225 microM, Cl(int) = 0.19 ml mg(-1) h(-1)) and was catalysed predominantly by CYP3A4. There was no apparent difference in the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in CYP2D6 EM and PM subjects. CYP3A4 is the major CYP enzyme catalysing the major metabolic pathway of dextropropoxyphene metabolism. Hence variability in the pharmacodynamic effects of dextropropoxyphene are likely due to intersubject variability in hepatic CYP3A4 expression and/or drug-drug interactions. Reported CYP2D6 phenocopying is not due to dextropropoxyphene being a CYP2D6 substrate.

Mucus as a barrier to the permeability of hydrophilic and lipophilic compounds in the absence and presence of sodium taurocholate micellar systems using cell culture models.

A mucus secreting CaCo-2-Ht29GlucH cell co-culture model was characterised and used to examine the influence of mucus as a barrier to the transport of hydrophilic and lipophilic compounds in the absence and presence of sodium taurocholate micellar (NaTC) systems. TEER measurements and permeability studies using the hydrophilic markers (mannitol, polyethylene glycols (PEGS) 900 and 4000) indicated that the paracellular permeability of the co-culture model was greater than that of the CaCo-2 model. At pH 7.4, no difference in the transport of a model lipophilic drug, dextropropoxyphene, was observed between the two models. However, at pH 4.5, when the drug was highly ionised the transport was significantly lower across the co-culture monolayers. NaTC micellar systems appeared to affect the different cell culture models in the order CaCo-2>CaCo-2-Ht29GlucH>Ht29GlucH. Following removal of the mucus layer by incubation with the mucolytic agent, N-acetyl-l-cysteine, the absorption enhancing potential of NaTC micellar systems was increased in the co-culture model.

Binding and hydrolysis of meperidine by human liver carboxylesterase hCE-1.

Human liver carboxylesterases catalyze the hydrolysis of apolar drug or xenobiotic esters into more soluble acid and alcohol products for elimination. Two carboxylesterases, hCE-1 and hCE-2, have been purified and characterized with respect to their role in cocaine and heroin hydrolysis. The binding of meperidine (Demerol) and propoxyphene (Darvon) was examined in a competitive binding, spectrophotometric assay. The hCE-1 and hCE-2 bound both drugs, with Ki values in the 0.4- to 1.3-mM range. Meperidine was hydrolyzed to meperidinic acid and ethanol by hCE-1 but not hCE-2. The Km of hCE-1 for meperidine was 1.9 mM and the kcat (catalytic rate constant) was 0.67 min-1. Hydrolysis of meperidine by hCE-1 was consistent with its specificity for hydrolysis of esters containing simple aliphatic alcohol substituents. Hence, hCE-1 in human liver microsomes may play an important role in meperidine elimination. Propoxyphene was not hydrolyzed by hCE-1 or hCE-2. This observation is consistent with the absence of a major hydrolytic pathway for propoxyphene metabolism in humans.

Propoxyphene and norpropoxyphene quantitation in the same solid-phase extraction using Toxi-Lab Spec VC MP3 system.

We have found that in using the Toxi-Lab Spec VC MP3 column we were able to easily identify and quantitate both propoxyphene and the major metabolite, norpropoxyphene, in a single extraction using urine as a matrix. Samples were screened using the Syva EMIT d.a.u. 1.0 assay for propoxyphene on the Olympus 5131, and all presumptive positives were prepared for confirmation by gas chromatography-mass spectrometry on Hewlett-Packard instruments. Urine (1.0 mL) was extracted and treated with a strong base (pH 11.0) in order to rearrange, by base catalysis, norpropoxyphene to norpropoxyphene amide, which chromatographs well on these columns.

Dopamine and dobutamine reduce myocardial d-propoxyphene content in experimentally intoxicated rats.

The effect of sympathomimetic intervention with dopamine or dobutamine on the myocardial uptake of d-propoxyphene was investigated experimentally in rats. The d-propoxyphene (19 mg kg-1 h-1) was continuously infused, intravenously, over 45 min. After 20 min of infusion the rats were given either dopamine (12.5 micrograms kg-1 min-1 or 25 micrograms kg-1 min-1), dobutamine (25 micrograms kg-1 min-1 or 45 micrograms kg-1 min-1) or normal saline (control). Each group consisted of eight rats. The myocardial d-propoxyphene content was significantly lower in the two groups given dopamine and in the group given dobutamine 45 micrograms kg-1 min-1 than in the control group (P less than 0.05). This finding indicates the benefit of early sympathomimetic intervention with either dopamine or dobutamine in d-propoxyphene intoxication.

Catastrophic neurologic signs due to drug interaction: Tegretol and Darvon.

Eight cases of carbamazepine toxicity from interaction with propoxyphene are reported. Serum concentrations of carbamazepine increased up to sixfold. All patients were symptomatic and two were hospitalized. Practitioners prescribing propoxyphene acutely for pain should be aware of this significant interaction.

The effect of ethanol intake on propoxyphene absorption and biotransformation in dogs.

The effect of ethanol (0.5 and 1.0 g/kg) on gastrointestinal absorption and presystemic biotransformation of propoxyphene (4 mg/kg) was studied in dogs in a crossover design. Low ethanol doses (0.5 g/kg) had no effect on the bioavailability of propoxyphene. High ethanol doses (1.0 g/kg) enhanced the bioavailability of orally administered propoxyphene significantly (p less than 0.05). With this dose of ethanol, the area under the blood concentration versus time curve (AUC)0-5 h of propoxyphene was approximately 200% of the control value. The level of norpropoxyphene, a major metabolite of propoxyphene, was significantly decreased (p less than 0.05) after administration of high ethanol doses. In all blood samples, after propoxyphene administration, an unidentified metabolite of propoxyphene was found, which formation was dose dependently inhibited by ethanol.

Toxicological studies in a Distalgesic addict.

The disposition and kinetics of paracetamol, dextropropoxyphene and their metabolites were investigated in an addict who claimed to be taking 80-100 Distalgesic tablets daily regularly. Plasma concentrations of paracetamol, dextropropoxyphene and their principal metabolites were measured after an oral dose of 15 Distalgesic tablets. The absorption of paracetamol and dextropropoxyphene was rapid with peak plasma concentrations at 15 and 30 min respectively. The elimination half-life for paracetamol was 2.3 h. Nordextropropoxyphene remained at steady state with very high plasma concentrations (5 mg/l). The urinary excretion of paracetamol and metabolites was not abnormal. The total recovery of paracetamol was only 31% of the dose. Apart from raised plasma gamma-glutamyltransferase activity there was no biochemical evidence for paracetamol-induced hepatocellular damage despite ingestion of 97.5 g of paracetamol over the 11 days of the withdrawal period.

Carbamazepine drug interactions.

Carbamazepine (CBZ) is commonly prescribed as an anticonvulsant or for the pain of trigeminal neuralgia. The potential for clinically important drug interactions exists because CBZ may induce the hepatic metabolism of other drugs or, conversely, other drugs may induce or inhibit the metabolism of CBZ. Studies and case reports demonstrate that CBZ may accelerate the metabolism of phenytoin, phenobarbital (PB), primidone, valproic acid, and warfarin. Likewise, phenytoin, PB, and primidone may increase the hepatic metabolism of CBZ. Inhibition of the metabolism of CBZ has been caused by triacetyloleandomycin, erythromycin, propoxyphene, isoniazid, and cimetidine. Future investigations will document the clinical significance of the CBZ interactions as well as reveal new interactions.

Comparison of the effects of therapeutic doses of meptazinol and a dextropropoxyphene/paracetamol mixture alone and in combination with ethanol on ventilatory function and saccadic eye movements.

The respiratory and psychomotor effects of a single oral dose of meptazinol (200 mg) and dextropropoxyphene (65 mg)/paracetamol (650 mg) mixture, was compared alone and in combination with ethanol (0.8 g kg-1). Peak saccade velocity following meptazinol or the dextropropoxyphene/paracetamol mixture was not significantly different from placebo. When each of the treatments was followed by ethanol administration, a significant decrease in saccade velocity (P less than 0.01) was seen. Given alone, neither of the analgesic drugs produced a significant change in the slope of the ventilatory response to hypercapnia. Ethanol did not affect the ventilatory response to hypercapnia when given alone or in combination with meptazinol, but when given with the dextropropoxyphene/paracetamol mixture, a significant reduction in the slope of the ventilatory response to hypercapnia occurred at 1.5 h (P less than 0.05) and 2 h (P less than 0.01) after administration of the analgesic drug. No pharmacokinetic interaction was demonstrated between ethanol and meptazinol or the dextropropoxyphene/paracetamol mixture in the doses used. In contrast to meptazinol, the dextropropoxyphene/paracetamol mixture interacts with ethanol on the ventilatory function.

The effects of naloxone on central hemodynamics and myocardial metabolism in experimental propoxyphene-induced circulatory shock.

The courses of the hemodynamic and cardiometabolic effects of naloxone were evaluated in propoxyphene-induced shock in eight pentobarbital-anesthetized pigs. Circulatory shock was induced by an infusion of propoxyphene chloride 15 mg . min-1 i.v. At shock, i.e. MAP less than 60 mmHg and/or CI less than 2.0 l . min-1 . m-2, naloxone was administered at 0.75, 1.5 and 3.0 mg . kg-1 with an interval between increments of 8 min. The propoxyphene infusion of 15 mg . min-1 was continued throughout the study. Following the injection of naloxone 0.75 mg . kg-1, increases were observed (% of baseline value) in MAP (41%), i.e. deficit to baseline 59%, HR (66%), CI (67%) and SVI (108%), whereas MPAP and MPAOP were unchanged. dP/dt increased (34%). In the coronary circulation naloxone initiated the following changes: CSF increased (69%) as did MVO2 (48%) with unchanged MO2-extraction, but CVR decreased further (36%). The maximum effects of naloxone were registered 2-3 min after 0.75 mg . kg-1. Following 1.5 and 3.0 mg . kg-1, no changes in hemodynamics were observed other than those caused by progressing propoxyphene intoxication.

Effect of oral charcoal and urine pH on dextropropoxyphene pharmacokinetics.

The effects of orally given activated charcoal, sodium bicarbonate and ammonium chloride on the pharmacokinetics of dextropropoxyphene were studied in six volunteers in a randomized, cross-over study. Serum and urine concentrations of dextropropoxyphene and norpropoxyphene were determined by GLC up to 72 h. Activated charcoal (50 g) given 5 min after dextropropoxyphene hydrochloride (130 mg), reduced its absorption by 97-99%. When given in repeated doses from 6 h on, 50 g followed by 12.5 g at 6 h intervals, charcoal significantly shortened the terminal serum half-life of dextropropoxyphene from 31.1 +/- 4.2 h to 21.2 +/- 3.1 h (p less than 0.05) and that of norpropoxyphene from 34.4 +/- 2.5 h to 19.8 +/- 3.4 h (p less than 0.001), and reduced their excretion into urine. The cumulative urinary excretion of unchanged dextropropoxyphene was increased 6-fold by acidification and reduced to 1/20 by alkalinization of urine, but the excretion of norpropoxyphene was much less dependent on urinary pH. However, the cumulative excretion of dextropropoxyphene and norpropoxyphene even into acidic urine accounted for less than 25% of the dose during 72 h. Because urinary pH has a great influence on the ratio of urinary versus serum dextropropoxyphene concentrations, pH should be taken into consideration, when the clinical significance of its concentration in urine is evaluated. Activated charcoal in high doses effectively prevents the absorption of that fraction of dextropropoxyphene which is in the stomach at the time of charcoal administration. Given in repeated oral doses, charcoal increases to some extent the rate of elimination of dextropropoxyphene and norpropoxyphene, probably by interrupting their enterohepatic or enteroenteric circulation.