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PubMed1991

Immobilization of microsomes into alginate beads is a convenient method for producing glucuronides from drugs.

The production of glucuronides from drugs by immobilized microsomal uridine diphosphate (UDP)-glucuronosyltransferase has been investigated. Of all the immobilization methods used (covalent binding, adsorption by ionic or hydrophobic interactions), only entrapment of microsomes into alginate beads in the presence of polyethyleneimine was effective in producing high glucuronidation rates, thus leading to the formation of large amounts of metabolites. The performance of the bioreactor was optimized with the drug 3'-azido-3'-deoxythymidine (AZT), active against the human immunodeficiency virus, as a model substrate of UDP-glucuronosyltransferase. Calcium (12 mM) could optimally improve the stability of microsomes entrapped in alginate beads. Upon immobilization, enzyme activation occurred, leading to a fivefold increase in specific activity. The determination of apparent Km and Vmax revealed that AZT was a better substrate for the immobilized enzyme than free microsomes. The AZT-glucuronide production obtained after 6 h was threefold higher than that observed with free microsomes. This bioreactor was also efficient in production of glucuronides from structurally different compounds such as bilirubin, 4-nitrophenol, clofibric acid, pirprofen, dextrorphan or morphine, the corresponding glucuronide of which possesses pharmacological or toxicological interest.

Alginates↗
PubMed1983

Three-choice drug discrimination: phencyclidine-like stimulus effects of opioids.

To assess the commonalities and differences in the discriminative stimulus properties of phencyclidine (PCP) and psychotomimetic opioids, rats were trained to discriminate PCP (2.0 mg/kg), cyclazocine (1.0 mg/kg), and saline in a three-choice discrete-trial avoidance paradigm. Stimulus control of behavior, defined as the reliable completion of 18 trials of a 20-trial session on the appropriate choice lever after administration of PCP, cyclazocine, or saline, was established in an average of 157 sessions. In tests of stimulus generalization, SKF-10,047 and dextrorphan engendered lever choices appropriate to both PCP and cyclazocine, sometimes in the same animal and at the same dose. The rats responded almost exclusively on the PCP-appropriate lever after ketamine and on the saline lever after morphine and d-amphetamine, indicating pharmacologic specificity. Naltrexone, in doses that had little effect on stimulus control of behavior by PCP, completely blocked cyclazocine-like stimulus control. Decreases in cyclazocine choices in the presence of naltrexone were associated with increases in PCP choices. These results support conclusions derived from two-choice procedures that psychotomimetic opioids have PCP-like stimulus effects, and provide direct evidence that these effects of cyclazocine are mediated by a component of action insensitive to an opiate antagonist.

Animals↗
PubMed1985

Specific opioid-amphetamine interactions in the caudate putamen.

Bilateral microinjection of morphine (0.003-3 micrograms/side) into the caudate putamen enhances the behavior induced by the IP injection of 1 mg/kg d-amphetamine phosphate in a dose-related manner. The duration of activity was prolonged and ambulation was changed to d-amphetamine stereotypy, a behavior normally associated with higher doses of d-amphetamine. The opioid activity was stereospecific in that levorphanol was active, whereas dextrorphan was not. The enhancement of d-amphetamine-induced behavior by the opioids was blocked by naloxone. D-ala2-met-Enkephalin also enhanced the amphetamine-induced behavior. This enhancement appears to be specific to the caudate putamen because the oral stereotypy observed appears to be a unique action of amphetamine in this region of the brain.

Amphetamine↗
PubMed1984

Ingestive behaviour of the pigeon: stereoselective influence of the opiate agonist levorphanol and its antagonism by naloxone.

Four experiments evaluated the effect of levorphanol on ingestive behaviour of different groups of non-deprived pigeons. In experiments 1 and 2, levorphanol and its (+)stereoisomer dextrorphan were administered at three doses (0.25, 1 and 2 mg). As compared with control values, levorphanol dose-dependently reduced food intake. This anorexia persisted for at least 5 h post-injection. A late hyperdipsia was also observed. These changes were stereoselective, suggesting that they followed the binding of levorphanol to opiate receptors. In experiments 3 and 4, the anorexic effect of 1 mg levorphanol, but not its hyperdipsic effect, was partly antagonized by the concomitant administration of either 0.25 mg or 1 mg naloxone. Given alone at the dose of 1 mg, naloxone slightly and transiently reduced food, but not water, intake. These results are discussed in terms of the endorphinergic regulation of ingestive behaviour in birds.

Animals↗
PubMed1980

Discriminative stimulus effects of pentobarbital in pigeons.

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0--17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6--17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3--3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.

Animals↗
PubMed1982

Discriminative stimulus effects of pentobarbital in rhesus monkeys: tests of stimulus generalization and duration of action.

Rhesus monkeys were trained to emit 20 or 30 consecutive responses on one lever following an IM injection of pentobarbital (10 or 18 mg/kg) and the same number of consecutive responses on another lever following an injection of saline. The required number of correct consecutive responses in both cases resulted in food delivery. When responding was reliably under the control of the presession injection, the ability of a variety of other compounds to produce pentobarbital-appropriate responding was examined. Diazepam, clobazam, methohexital, pentobarbital, and phenobarbital, given 10 or 20 min before the session, produced dose-related pentobarbital-appropriate responding in each monkey. Ethylketazocine and dextromethorphan produced responding primarily on the saline-appropriate lever, whereas codeine, cyclazocine, dextrorphan, and ketamine resulted in responding that was, on the average, intermediate between that appropriate for pentobarbital and that appropriate for saline. When tested at various times after their injection, methohexital (3.2 mg/kg) and pentobarbital (10 mg/kg) produced pentobarbital-appropriate responding within 10 min. Barbital (56 mg/kg) resulted in pentobarbital-appropriate responding only if at least 1 h intervened between the injection and the experimental session. The discriminative effects of methohexital, pentobarbital, and barbital lasted approximately 20-60, 120-240, and 480-720 min, respectively. The time-course of the discriminative stimulus effects of barbiturates in the rhesus monkey appears to parallel closely other pharmacological actions of these compounds.

Animals↗
PubMed1982

Discriminative stimulus properties of narcotic and non-narcotic drugs in rats trained to discriminate opiate kappa-receptor agonists.

The purpose of this study was to evaluate the discriminative stimulus properties of some narcotic and non-narcotic drugs in rats trained to discriminate the effect of the proposed opiate kappa-receptor agonists ethylketocyclazocine and bremazocine. Male Sprague-Dawley rats were trained in a two-lever food-reinforced paradigm to discriminate between the effect of ethylketocyclazocine (0.32 mg/kg) or bremazocine (0.04 mg/kg) and saline. Both groups of trained rats showed dose-dependent generalization to the effect of the proposed kappa-agonist MRZ-2033 and some animals generalized the effect of nalorphine and pentazocine. Some ethylketocyclazocine - but no bremazocine - trained rats generalized the effect of buprenorphine. The effect of dextrorphan, phencyclidine, and ketamine was generalized by some bremazocine -, but no ethylketocyclazocine-trained rats. Neither group of rats generalized the effect of etorphine, haloperidol, diazepam, or pentobarbital. These data suggest the usefulness of this procedure to evaluate the kappa-like properties of opioid drugs.

Animals↗
PubMed1980

Opioid receptors in the caudate nucleus can mediate EMG-recorded rigidity in rats.

Systemic administrations of opioids are known to induce "catatonia" or "lead pipe rigidity" in rats. The relevance of the caudate nucleus in inducing rigidity was tested. For this purpose, several opioids (or saline) were injected into the head of the caudate nucleus ("intrastriatal" injection) through an implanted cannula, and the electromyographical activity (EMG) was recorded in the gastrocnemius-soleus muscle (GS). Morphine (7.5-3.0 microgram), injected unilaterally, induced a continuous EMG activity in the ipsilateral GS muscle. This effect could be antagonized by systemic administration of naloxone (1 or 2 mg/kg i.p.). D-ala2-met5-enkephalinamide (3 microgram) and levorphanol (22.5 microgram) induced an EMG activity, too, whereas an equimolar dose of dextrorphan was ineffective, indicating that this effect was stereospecific and mediated via opioid receptors in the caudate nucleus. The EMG activity observed after systemic morphine administration (15 mg/kg i.p.) was antagonized by intrastriatal injection of naloxone (5 microgram). From our results, it can be concluded that the striatum--at least the head of the caudate nucleus--plays an important role in mediating the rigidity observed after systemic administration of morphine and other opioids.

Animals↗
PubMed1978

Interactions of opiates and prostaglandins E with regard to cyclic AMP in striatal tissue of rats in vitro.

The effects of prostaglandins E on the concentration of cyclic AMP (cAMP) and a possible antagonism of opiates vs. prostaglandins E were studied in homogenates and in slices of rat striata in vitro. In homogenates, PGE1 or PGE2 did not affect the synthesis of cAMP. Morphine slightly lowered the cAMP synthesis, in presence or absence of PGE1 or PGE2. In slices, PGE2 significantly elevated the cAMP concentrations, either in presence or in absence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Morphine, met-enkephalin and levorphanol, but not dextrorphan, antagonized this rise of cAMP. The effect of morphine was antagonized by naloxone. Adenosine or an elevation of K+-ions raised the cAMP concentrations, and PGE2 induced a further increase. In presence of elevated K+-ions or adenosine, however, morphine did not antagonize the PGE2-induced rise of cAMP concentration. It is suggested that under some experimental conditions described in the literature, endogenous activators of cAMP formation, e.g. adenosine, might mask the inhibitory effect of opiates on stimulation of opiates on stimulation of cAMP synthesis induced by prostaglandins E.

Animals↗
PubMed1994

Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists.

Behavioral effects of PCP-type noncompetitive antagonists of N-methyl-D-aspartate (NMDA) receptors overlap with those of a host of other centrally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were used to differentiate PCP-type non-competitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (-)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine] produced dose-related increases in locomotor activity and the percentage of mice falling off an inverted, elevated wire mesh screen. Both effects demonstrated stereoselectivity, occurred at comparable dose levels, and were within the range of doses producing other biological effects (e.g., anticonvulsant). The potencies of these drugs for producing behavioral effects were positively correlated with affinities for PCP ([3H]MK-801) but not sigma([3H]SKF 10,047) receptors. Although muscarinic antagonists (benactyzine, atropine) produced effects in the same direction, locomotor stimulation was small and occurred at lower doses than those inducing screen failures. Competitive NMDA antagonists (LY 274614, LY 233536, CPP, NPC 12626), sigma receptor ligands (DTG, dextromethorphan), postsynaptic dopamine agonists (quinpirole, SKF 38393) and antagonists (haloperidol, SCH 39166), and some depressant compounds (morphine, diazepam) increased failures on the screen test but decreased locomotor activity. Ligands of the polyamine regulatory site of the NMDA receptor (ifenprodil, SL 82.0715-10) and the AMPA receptor antagonist NBQX decreased locomotor activity without increasing screen failures. An antagonist of the strychnine-insensitive glycine receptor (7-chlorokynurenic acid) did not affect performance on either test. Psychomotor stimulants (cocaine and methamphetamine) stimulated locomotor activity without affecting screen performance. The only false positives occurred with barbiturates (pentobarbital, phenobarbital). Nonetheless, the present procedure demonstrates excellent sensitivity and power for rapid discrimination of uncompetitive NMDA antagonists.

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

Dextromethorphan metabolism in Jordanians: dissociation of dextromethorphan O-demethylation from debrisoquine 4-hydroxylation.

The concentrations of dextromethorphan (DM) and its metabolites dextrorphan (DRP), 3-methoxymorphinan (MM) and 3-hydroxymorphinan (HM) were measured in 8 h urine samples from 266 unrelated healthy Jordanian subjects following oral administration of 30 mg dextromethorphan hydrobromide and using a rapid, sensitive and precise HPLC method with fluorometric detection. The frequency of the 'poor' metabolizer status of DM-O-demethylation as judged by log DM/DRP was found to be 6.8% with a 95% confidence interval of 3.8-9.8%. There was a strong correlation between log DM/DRP and log total non-O-demethylated compounds (NODM)/total O-demethylated metabolites (ODM) metabolic ratios (r = 0.96, P < 0.01). However, one subject with log DM/DRP of 0.05 that classifies him as a poor metabolizer was found to have a log NODM/ODM of -0.73 which is in the range of extensive metabolizer status suggesting the presence of another cytochrome P450 isoenzyme involved in dextromethorphan O-demethylation. Dextromethorphan N-demethylation to 3-methoxymorphinan was detected in 55.3% of individuals. Furthermore, a dissociation between dextromethorphan O-demethylation and debrisoquine (D) 4-hydroxylation has been observed. Among the 116 subjects phenotyped with both dextromethorphan and debrisoquine, 7 were poor metabolizers of both, three were poor metabolizers of debrisoquine and extensive metabolizers of dextromethorphan whilst 4 were poor metabolizers of dextromethorphan and extensive metabolizers of debrisoquine, one of whom was reclassified as an extensive metabolizer of dextromethorphan using log NODM/ODM to characterize dextromethorphan metabolizer status.

Adolescent↗
PubMedDate not supplied

Effect of methamphetamine on the pharmacokinetics of dextromethorphan and midazolam in rats.

Methamphetamine is the fourth most frequently reported compound associated with drug abuse on admission of patients to treatment centres after cocaine, heroin and marijuana. It is metabolized in the organism with a reaction that is catalyzed by cytochrome P450, mainly by the CYP2D and CYP3A subfamily, 4-hydroxyamphetamine and amphetamine being dominant metabolites. The present pharmacokinetic study was undertaken to investigate the possible influence of methamphetamine (10 mg/kg, i.p., once daily for six days) on the pharmacokinetics of dextromethorphane as a model substrate for rat cytochrome P-4502D2 and midazolam as a model substrate for CYP3A1/2. Animals received a single injection of dextromethorphane (10 mg/kg) or midazolam (5 mg/kg) in the tail vein 24 h after the last dose of methamphetamine or administration of placebo. The results of pharmacokinetic analysis showed a significantly increased rate of dextrorphane and 3-hydroxymorphinan formation, and a marked stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam's metabolic conversion to hydroxy derivates of midazolam indicated a significant increase in CYP3A1/2 activity. The results showed that the administration of methamphetamine significantly stimulated the metabolic activity of CYP2D2 as well as that of CYP3A1/2. With regard to the high level of homology between human and rat CYP isoforms studied, the results may have a clinical impact on future pharmacotherapy for methamphetamine abuse.

Alcohol Oxidoreductases↗
PubMed2000

Antiparkinsonian and antidyskinetic activity of drugs targeting central glutamatergic mechanisms.

Motor dysfunction produced by the chronic non-physiological stimulation of dopaminergic receptors on striatal medium spiny neurons is associated with alterations in the sensitivity of glutamatergic receptors, including those of the N-methyl-D-aspartate (NMDA) subtype. Functional characteristics of these ionotropic receptors are regulated by their phosphorylation state. Lesioning the nigrostriatal dopamine system of rats induces parkinsonian signs and increases the phosphorylation of striatal NMDA receptor subunits on serine and tyrosine residues. The intrastriatal administration of certain inhibitors of the kinases capable of phosphorylating NMDA receptors produces a dopaminomimetic motor response in these animals. Treating parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the serine and tyrosine phosphorylation of specific NMDA receptor subunits. Again, the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases alleviates the motor complications. NMDA receptor antagonists, including some non-competitive channel blockers, act both palliatively and prophylactically in rodent and primate models to reverse these levodopa-induced response alterations. Similarly, in clinical studies dextrorphan, dextromethorphan, and amantadine have been found to be efficacious against motor complications. Recent observations in animal models further indicate that certain amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists alleviate, while others exacerbate, these complications. Thus, it appears that the denervation or intermittent stimulation of striatal dopaminergic receptors differentially activates signal transduction pathways in medium spiny neurons. These in turn modify the phosphorylation state of ionotropic glutamate receptors and consequently their sensitivity to cortical input. These striatal changes contribute to symptom production in Parkinson's disease, and their prevention or reversal could prove useful in the treatment of this disorder.

Animals↗
PubMed1997

Dizocilpine-like discriminative stimulus effects of competitive NMDA receptor antagonists in mice.

Several non-competitive NMDA receptor ion channel blockers, competitive NMDA antagonists and compounds acting at other sites on the NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of dizocilpine. Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor antagonist, dizocilpine (0.17 mg/kg), from saline in a T-maze. Mice rapidly acquired the discrimination with minimal amounts of drugs required for training and testing. Several non-competitive antagonists dose-dependently substituted for dizocilpine with a rank order of potency of dizocilpine > TCP > (-)-MK-801 > SKF 10,047 > dextrorphan > PCP. There was a positive correlation between the potencies of the compounds that substituted for dizocilpine and their previously reported affinities for the [3H]dizocilpine binding site of the NMDA receptor ion channel. Compounds acting at other sites on the NMDA receptor complex, including NMDA, the partial agonist at the strychnine-insensitive glycine site, ACPC, and the polyamine antagonist, ifenprodil, failed to substitute fully. In addition, the AMPA antagonist, NBQX, the monoamine uptake inhibitor, cocaine, and the GABAA receptor agonists, diazepam and phenobarbital, failed to substitute fully for dizocilpine. However, like the ion channel blockers, the competitive NMDA antagonists, CGS 19755, NPC 17742, (+/-)CPP and LY 233536 dose-dependently substituted for dizocilpine. The competitive antagonist, LY 274614, and its active enantiomer, LY 235959, failed to substitute for dizocilpine, each producing severe disruptions in locomotor activity. That most of the competitive antagonists substituted for dizocilpine is in accordance with other behavioral data (e.g., ataxia, locomotor activity) documenting similarities in the effects of non-competitive and competitive antagonists. These findings are also consistent with results of clinical investigations suggesting overlap in the behavioral and subjective profiles of competitive and non-competitive NMDA blockers.

Animals↗
PubMed1998

Inhibition of dextromethorphan metabolism by moclobemide.

This pilot study was conducted to evaluate the potential of the new antidepressant moclobemide to inhibit the cytochrome enzyme P4502D6 (CYP2D6) using the cough suppressant dextromethorphan as a substrate in four extensive metabolizers (EM) of debrisoquine. The subjects received seven oral doses of 20 mg dextromethorphan at 4-h intervals over 2 days (1 and 2) and subsequently moclobemide (300 mg b.i.d.) for 9 days. On days 10 and 11, they received seven doses of 20 mg dextromethorphan in addition to moclobemide. During monotreatment and combined treatment, blood was collected on days 2 and 11, respectively, for determination of dextromethorphan and its demethylated metabolites using automated high-performance liquid chromatography with column switching. Concurrent administration of moclobemide markedly reduced the O-demethylation of dextromethorphan, whereas the N-demethylation of dextrorphan to hydroxymorphinan was not affected. The findings indicate that moclobemide can affect the pharmacokinetics of drugs that are mainly metabolized by CYP2D6.

Adolescent↗
PubMed2005

Measurement of CYP2D6 and CYP3A4 activity in vivo with dextromethorphan: sources of variability and predictors of adverse effects in 419 healthy subjects.

OBJECTIVE: Dextromethorphan (DEM) shares part of the adverse event profile of opioids and is widely used as a probe drug for CYP2D6 phenotyping and for the assessment of CYP2D6 activity. It has also been used to assess CYP3A4 activity. This study examined the influence of anthropometric variables, oral contraceptives, smoking habits, mu-opioid receptor and MDR1 genetic polymorphisms and components of the DEM ratios on the variability of CYP2D6 and CYP3A4 metabolic ratios and on the occurrence of adverse events following DEM administration. METHODS: This was a retrospective analysis of a database in 419 healthy subjects. CYP2D6 and CYP3A4 metabolic ratios were measured as the log of the ratios of the amount of DEM to the amount of dextrorphan (DOR) and of the amount of DEM to the amount of 3-methoxy-morphinan (MET) excreted in urine during a 12-h time period, respectively, following the oral administration of 80 mg of dextromethorphan hydrobromide. Logistic regression was performed to examine the factors associated with changes in metabolic ratios and with the occurrence of adverse events. RESULTS: The CYP2D6 metabolic ratio allowed identification of extensive and poor metabolizers of DEM. The CYP2D6 and CYP3A4 metabolic ratios were not strictly independent one from each other. Based on multivariate analysis, the CYP2D6 metabolic ratio was a stronger independent predictor of adverse events (p<0.0001) than the CYP2D6 phenotype (p=0.05). Anthropometric variables, oral contraceptives, smoking habits, mu-opioid receptor and MDR1 genetic polymorphisms did not significantly contribute to changes in metabolic ratios or to the occurrence of adverse events. CONCLUSIONS: Dextromethorphan can be used for CYP2D6 phenotyping, but the CYP2D6 and CYP3A4 metabolic ratios are not strictly independent one from each other. The CYP2D6 metabolic ratio predicts adverse events to DEM as does CYP2D6 phenotype, and extensive metabolizer subjects are not protected against adverse events.

Adult↗
PubMed2000

In-vivo indices of CYP2D6 activity: comparison of dextromethorphan metabolic ratios in 4-h urine and 3-h plasma.

OBJECTIVES: Dextromethorpan (DM) is widely used as a probe drug to assess in vivo the activity of the cytochrome P450 2D6 (CYP2D6). The aim of the study was to compare metabolic ratios (MRs) of DM to dextrorphan (DEX) in plasma and urine. We examined, separately in urine and plasma, the relationships between the MRs which are based on DEX and those involving the sum of DEX and a secondary metabolite hydroxymorphinan (HM). Furthermore, we compared the MRs in plasma obtained with and without hydrolysis of DEX glucuronides. METHODS: Concentrations of DM and metabolites in urine and plasma were determined by HPLC after a single oral dose of 30 mg DM hydrobromide to 101 healthy Caucasian subjects. Urine was collected over the time interval 0-4 h after the dose and plasma was obtained from 95 subjects 3 h after administration. RESULTS: Six subjects (5.9%) were of poor metaboliser (PM) phenotype (urinary DM:DEX ratio >0.3). A good correlation (r2 = 0.777, P < 0.00001) was observed between the metabolic ratios of DM:DEX in plasma and urine. There was an excellent correlation, both in plasma and urine, between the log-transformed ratios of DM:DEX and of DM to the sum of molar concentrations of DEX and HM (r2 > 0.996, P < 0.00001). Plasma samples of 89 subjects (83 EM and 6 PM) were analyzed without deconjugation of DEX glucuronide also. The correlation between the plasma ratios of DM:DEX based on unconjugated DEX and those involving glucuronide (r2 = 0.793, P < 0.00001) was comparable to that reported by other authors on urine. CONCLUSION: In healthy Caucasian subjects, the MRs of DM to DEX in plasma obtained at 3 h correlated reasonably well with those in urine collected over the time interval 0-4 h after the dose. Nevertheless, repeatability of this plasma index should be determined before its wide use can be recommended. Finally, the interindividual variation in DEX metabolism to HM (catalyzed by CYP3A) contributes only minimally to the interindividual variability of the MRs.

Adult↗
PubMedDate not supplied

Genetic polymorphism of CYP2D6 in North Indian subjects.

OBJECTIVES: CYP2D6 polymorphism of clinical relevance occurs with variable frequency in different ethnic groups. Since this polymorphism has not been studied in a North Indian population, the present study was undertaken. METHODS: One hundred healthy unrelated North Indian subjects received 30 mg dextromethorphan (DM) orally at bed-time. The amounts of DM and its metabolite, dextrorphan (DR), excreted in 8 h urine were estimated by high performance liquid chromatography. Metabolic ratio (DM/DR excreted in 8 h) was used as an index of the metabolic status of an individual. RESULTS: The analysis of the data by frequency distribution histogram, probit and NTV plots demonstrated bimodal distribution of the North Indian subjects with respect to hepatic CYP2D6. Out of 100 subjects, 97 were extensive metabolizers (EMs), whereas three were poor metabolizers (PMs). EMs and PMs excreted 29.82 and 2.67 micromol DR (mean value) and 2.59 and 8.82 micromol DM (mean value) in 8 h, respectively. MR and log MR was 197- and 2.2-fold higher in PMs versus EMs. The antimode value of zero was determined by visual observation in frequency distribution histogram and inflection point in probit plot. CONCLUSION: From this study, it can be concluded that the PM phenotype of CYP2D6 occurs with a frequency of 3% (95% confidence interval of 0.33%-6.33%) in North Indians.

Adolescent↗