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Biological Psychiatry Oct 1993Changes in plasma homovanillic acid (HVA) were investigated in neuroleptic responsive and nonresponsive schizophrenics in order to delineate parameters of dopamine... (Clinical Trial)
Clinical Trial
Changes in plasma homovanillic acid (HVA) were investigated in neuroleptic responsive and nonresponsive schizophrenics in order to delineate parameters of dopamine regulation, which may underlie differences in neuroleptic responsivity. Nineteen schizophrenics were treated with haloperidol for 6 weeks. HVA was sampled at baseline, 24 hr after initial neuroleptic dose, and after 6 weeks of treatment. Subjects were pretreated with debrisoquin in order to reduce the peripheral production of HVA. The responders had an initial rise in HVA at 24 hr after first neuroleptic dose, followed by a decline back to baseline over the 6 weeks of treatment. The nonresponders' HVA failed to rise at 24 hr after first neuroleptic dose. At 6 weeks of treatment their HVA had fallen to significantly below baseline. Thus, a rise in HVA 24 hr after the first dose of neuroleptic predicted treatment response; a fall in HVA at 6 weeks to below pretreatment values was associated with neuroleptic nonresponse.
Topics: Adult; Analysis of Variance; Dose-Response Relationship, Drug; Drug Administration Schedule; Haloperidol; Homovanillic Acid; Humans; Male; Psychiatric Status Rating Scales; Psychometrics; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology
PubMed: 8274579
DOI: 10.1016/0006-3223(93)90194-i -
British Journal of Clinical Pharmacology Nov 1994A mephenytoin test was carried out in 106 unrelated healthy Turkish volunteers. Racemic mephenytoin was coadministered with either debrisoquine or sparteine. The S/R... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
A mephenytoin test was carried out in 106 unrelated healthy Turkish volunteers. Racemic mephenytoin was coadministered with either debrisoquine or sparteine. The S/R mephenytoin ratio ranged from < 0.1 to 0.73 in 105 subjects, accordingly phenotyped as extensive metabolisers. One subject had an S/R mephenytoin ratio of 1.02, showing that he was a poor metaboliser of mephenytoin (0.94%, confidence interval 0.25% and 13.65%). In 48 subjects, the metabolic ratios of debrisoquine and sparteine were correlated significantly (rs = 0.61, P < 0.001).
Topics: Adolescent; Adult; Cohort Studies; Debrisoquin; Female; Health Personnel; Humans; Male; Mephenytoin; Middle Aged; Oxidation-Reduction; Polymorphism, Genetic; Sparteine; Stereoisomerism; Turkey; White People
PubMed: 7893589
DOI: 10.1111/j.1365-2125.1994.tb04383.x -
British Journal of Clinical Pharmacology Jul 1986The effects of antipyrine (1200 mg day-1), phenobarbitone (100 mg day-1) and rifampicin (600 mg and 1200 mg day-1, respectively) administration for 7 days on sparteine... (Comparative Study)
Comparative Study
The effects of antipyrine (1200 mg day-1), phenobarbitone (100 mg day-1) and rifampicin (600 mg and 1200 mg day-1, respectively) administration for 7 days on sparteine metabolism and 6 beta-hydroxycortisol excretion were studied in panels of extensive (EM) and poor metaboliser (PM) subjects. Drug metabolism was induced in both EM and PM subjects by antipyrine and rifampicin pretreatment as indicated by increased excretion of 6 beta-hydroxycortisol. A 30% increase in metabolic clearance of sparteine was observed in EM subjects following rifampicin administration whereas in PM subjects no effect on the overall elimination of the drug was seen. The data indicate that the regulation of cytochrome P-450 isozyme involved in polymorphic debrisoquine/sparteine metabolism is predominantly under genetic control and that enzyme induction exerts only a marginal effect.
Topics: Adult; Antipyrine; Enzyme Induction; Female; Half-Life; Humans; Hydrocortisone; Male; Metabolic Clearance Rate; Middle Aged; Oxidation-Reduction; Phenobarbital; Rifampin; Sparteine
PubMed: 3741726
DOI: 10.1111/j.1365-2125.1986.tb02879.x -
British Journal of Clinical Pharmacology Nov 19901. Three oxidations of the enantiomers of propranolol were studied in human liver microsomes under two reaction conditions. Previous in vitro studies had established...
1. Three oxidations of the enantiomers of propranolol were studied in human liver microsomes under two reaction conditions. Previous in vitro studies had established that two of the livers were from poor metaboliser (PM) phenotypes for the debrisoquine 4-hydroxylase (cytochrome P-450IID6) and the remaining seven were from extensive metaboliser (EM) phenotypes. 2. In the presence of NADPH and oxygen 4- and 5-hydroxylation of propranolol occurred in microsomes from all nine livers, as did propranolol N-desisopropylation. R(+)-propranolol was oxidized preferentially along the three pathways, although enantioselectivity observed for N-desisopropylation may have arisen not only from stereoselectivity in formation rates, but also from stereoselectivity in subsequent microsomal metabolism, possibly by monoamine oxidase. The involvement of monoamine oxidase in the further microsomal metabolism of N-desisopropylpropranolol was indicated by inhibition of the metabolism of this compound when incubated with phenelzine. 3. Cumene hydroperoxide has been proposed to support only the activity of cytochrome P450IID6. This is consistent with the observations that a) propranolol 4- and 5-hydroxylation occurred in microsomes from the EM livers only and b) side-chain oxidation was not observed under these conditions in either PM or EM livers. 4. Using cumene hydroperoxide to support the reactions, the 4-hydroxylation of propranolol showed little enantioselectivity, whereas S(-)-propranolol was 5-hydroxylated about twice as fast as the R(+)-enantiomer. There were highly significant correlations between the rates of 4- and 5-hydroxylation of R(+)-propranolol (r = 0.96, P less than 0.001, n = 7 livers) and of S(-)-propranolol (r = 0.98, P less than 0.001). Both oxidations were described by single-site Michaelis-Menten kinetics. 5. The findings suggest that P450IID6 is involved in both the 4- and 5-hydroxylations of propranolol, but that these metabolites can also be formed by other P450 isoenzymes. It is confirmed that P450IID6 does not contribute to the N-desisopropylation of propranolol. Furthermore, the finding that mephenytoin did not inhibit the appearance of this metabolite is not consistent with the results of in vivo studies suggesting the involvement of the same enzyme in the side-chain oxidation of propranolol and the 4-hydroxylation of mephenytoin.
Topics: Benzene Derivatives; Humans; Hydroxylation; Isoenzymes; Microsomes, Liver; Oxidation-Reduction; Phenotype; Propranolol; Stereoisomerism; Substrate Specificity
PubMed: 2271375
DOI: 10.1111/j.1365-2125.1990.tb03846.x -
Life Sciences 1991The DM1/sigma 1 site binds dextromethorphan (DM) and sigma receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution...
The DM1/sigma 1 site binds dextromethorphan (DM) and sigma receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [3H]dextromethorphan, [3H]3-(-3-Hydroxyphenyl)-N-(1-propyl)piperidine and (+)-[3H]1,3-Di-o-tolyl-guanidine ([3H]DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM Ki values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM1/sigma 1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed Ki values of 9-13 and 3-4 microM respectively against the three labeled ligands. These results, the broad specificity of the DM1/sigma 1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor. These findings may have important implications for the understanding of the therapeutic, side effects and toxicity of several neurotropic drugs.
Topics: Animals; Binding, Competitive; Brain; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Debrisoquin; Dextromethorphan; Guinea Pigs; Kinetics; Ligands; Lobeline; Mixed Function Oxygenases; Neurotransmitter Uptake Inhibitors; Piperazines; Proadifen; Receptors, Opioid; Receptors, sigma; Sparteine
PubMed: 1846936
DOI: 10.1016/0024-3205(91)90469-r -
British Medical Journal Sep 1966
Topics: Adult; Aged; Amidines; Antihypertensive Agents; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged
PubMed: 5917390
DOI: 10.1136/bmj.2.5516.728 -
British Journal of Clinical Pharmacology Feb 19891. The interindividual differences in serum concentrations of dextromethorphan (DM) and its metabolites were studied in 29 healthy subjects given 120 mg orally. They... (Clinical Trial)
Clinical Trial
1. The interindividual differences in serum concentrations of dextromethorphan (DM) and its metabolites were studied in 29 healthy subjects given 120 mg orally. They were also phenotyped according to the urinary ratio of debrisoquine and 4-hydroxy-debrisoquine. 2. Four (14%) subjects were found to be poor metabolizers (PM) with a dextromethorphan/dextrorphan metabolite ratio in plasma of 3.6 or more compared with extensive metabolizers (EM) with a ratio of 0.11 or less. Significant levels of 3-hydroxymorphinan were measurable in all individuals except two, both of whom were PMs. This subdivision corresponded to the phenotype determined by the metabolic ratio of debrisoquine (r = 0.92). 3. Twelve of the 29 subjects reported adverse drug reactions after dextromethorphan administration compared with none after placebo.
Topics: Adult; Automobile Driving; Debrisoquin; Dextromethorphan; Dextrorphan; Double-Blind Method; Humans; Levorphanol; Noscapine; Phenotype; Random Allocation
PubMed: 2713216
DOI: 10.1111/j.1365-2125.1989.tb05354.x -
British Journal of Clinical Pharmacology Oct 19911. The relationship between the metabolism of the antiarrhythmic drug mexiletine and the debrisoquine/sparteine-type polymorphism was studied in vitro, using microsomes...
1. The relationship between the metabolism of the antiarrhythmic drug mexiletine and the debrisoquine/sparteine-type polymorphism was studied in vitro, using microsomes from six human livers, and in vivo, in nine healthy drug-free volunteers with wide variation in their ability to hydroxylate debrisoquine. 2. There was a strong and similar correlation between the formation rate of both major mexiletine metabolites, p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), and the high affinity component of dextromethorphan O-demethylase activity in human liver microsomes (rs = 0.94; P less than 0.01). 3. There were marked interindividual differences in the amounts of PHM and HMM excreted in the urine over 48 h after a single 200 mg oral dose of mexiletine hydrochloride. Recoveries of both metabolites were correlated inversely with the debrisoquine/4-hydroxydebrisoquine (D/HD) urinary metabolic ratio (rs = -0.83; P = 0.006 and rs = -0.85; P = 0.004, respectively) and were lower in poor metabolisers of debrisoquine (PM) than in extensive metabolisers (EM). Moreover, PM had the highest values of mexiletine/PHM and mexiletine/HMM urinary ratios. In addition, there was a strong correlation between these two indices of mexiletine hydroxylation and the D/HD metabolic ratios (rs = 0.92; P = 0.001 and rs = 0.90; P = 0.001, respectively). 4. After mexiletine pretreatment, the values for D/HD ratio were significantly increased in EM while corresponding values in PM were similar. 5. These findings are in accordance with previous in vitro data suggesting that PHM and HMM formation is predominantly catalyzed by the genetically variable human liver cytochrome P450IID6 isoenzyme responsible for the debrisoquine/sparteine-type polymorphism of drug oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adult; Debrisoquin; Female; Humans; Hydroxylation; Male; Mexiletine; Phenotype; Polymorphism, Genetic; Smoking; Sparteine
PubMed: 1958440
DOI: 10.1111/j.1365-2125.1991.tb03931.x -
British Journal of Clinical Pharmacology Dec 1985The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. The log10 metoprolol to alpha-hydroxymetoprolol urinary ratio was...
The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. The log10 metoprolol to alpha-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P less than 0.001). The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. The major urinary metabolite of metoprolol metabolism was H117-04, the end-product of O-dealkylation. The distribution of the log10 metoprolol to H117-04 (M/H117-04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P less than 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. These results indicate that both the alpha-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. In a sub-group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post-exercise heart rate at 24 h after dosing.
Topics: Adrenergic beta-Antagonists; Adult; Aged; Biotransformation; Dealkylation; Debrisoquin; Female; Humans; Isoquinolines; Male; Metoprolol; Middle Aged; Oxidation-Reduction; Pedigree; Phenotype; Polymorphism, Genetic
PubMed: 2868742
DOI: 10.1111/j.1365-2125.1985.tb05112.x -
British Journal of Clinical Pharmacology Sep 2003To determine CYP2C19 and CYP2D6 activity in patients with multiple sclerosis (MS) before and during interferon (IFN)-beta treatment.
AIMS
To determine CYP2C19 and CYP2D6 activity in patients with multiple sclerosis (MS) before and during interferon (IFN)-beta treatment.
METHODS
CYP2C19 and CYP2D6 activities were assessed using the probe drugs mephenytoin and debrisoquine, respectively. Urinary mephenytoin (S/R) and debrisoquine (debrisoquine/hydroxy-debrisoquine) metabolic ratios (MR) were determined in 10 otherwise healthy Caucasian multiple sclerosis (MS) patients in the initial stage of the disease, prior to and 1 month after commencing treatment with IFN-beta (Avonex, Rebif or Betaferon). In addition, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, and CYP2D6*5 genotyping was performed.
RESULTS
There was no significant difference in the (S)/(R) mephenytoin ratio (mean difference 0.04; 95% CI -0.03, 0.11) or the debrisoquine MR (mean difference 0.29; 95% CI -0.44, 1.02) before and during regular IFN-beta treatment in extensive metabolizers (EM) (P = 0.5 and P = 0.4 for the respective probe drugs; n = 9 subjects). There were also no differences between the different IFN-beta treatments (P = 0.6 for the (S)/(R) mephenytoin ratio and P = 0.7 for the debrisoquine MR; anova; n = 10).
CONCLUSIONS
IFN-beta treatment did not affect the activity of CYP2C19 or CYP2D6. The results suggest that it is safe to administer CYP2C19 or CYP2D6 substrates, without dose adjustment, to patients treated with IFN-beta.
Topics: Adult; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Female; Genotype; Humans; Interferon-beta; Male; Middle Aged; Mixed Function Oxygenases; Multiple Sclerosis; Phenotype
PubMed: 12919185
DOI: 10.1046/j.0306-5251.2003.01859.x