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British Journal of Pharmacology Aug 19951. The effect of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') and its N-demethylated product, 3,4-methylenedioxyamphetamine (MDA) on both...
The hyperthermic and neurotoxic effects of 'Ecstasy' (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype.
1. The effect of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') and its N-demethylated product, 3,4-methylenedioxyamphetamine (MDA) on both rectal temperature and long term neurotoxic loss of cerebral 5-hydroxytryptamine (5-HT) has been studied in male and female Dark Agouti (DA) rats. The female metabolizes debrisoquine more slowly than the male and its use has been suggested as a model of the human debrisoquine 4-hydroxylase poor metabolizer phenotype. 2. A novel h.p.l.c. method was developed and used to measure plasma MDMA and MDA concentrations in the DA rats. 3. The hyperthermic response following MDMA was enhanced in female rats. Plasma MDMA concentrations were also 57% higher than in males 45 min post-injection, while plasma concentrations of MDA were 48% lower. 4. Plasma concentrations of MDMA and MDA in male rats were unaffected by pretreatment with proadifen (15 mg kg-1) or quinidine (60 mg kg-1), but the hyperthermic response to MDMA (10 mg kg-1, i.p.) was enhanced by quinidine pretreatment. 5. The hyperthermic response following MDA was greater in male DA rats, despite plasma drug concentrations being 40% higher in females 60 min after injection. 6. Seven days after a single dose of MDMA (10 mg kg-1, i.p.) there was a substantial loss in the concentration of 5-HT and 5-hydroxyindoleacetic acid (5-HIA) in cortex and hippocampus. [3H]-paroxetine binding was also decreased by 27% in the cortex, indicating that the amine loss reflected a neurodegenerative change. MDMA (5 mg kg-1, i.p.) was without effect on brain 5-HT content. content.7. A single dose of MDA (5 mg kg-1, i.p.) produced a major (approximately 40%) loss of 5-HT content of cortex and hippocampus 7 days later. The loss was similar in males and females.8 These data demonstrate that female DA rats are more susceptible to the acute hyperthermic effects ofMDMA, probably because of impaired N-demethylation and indicate that in human subjects acuteMDMA-induced toxicity may be exacerbated in poor metabolizer phenotypes. Low debrisoquine hydroxylase activity did not appear to impair the formation of a MDMA or MDA neurotoxic metabolite. Both severe acute hyperthermia and delayed neurotoxicity occurred following plasma levels of MDMA comparable to those reported in persons misusing the drug.
Topics: 3,4-Methylenedioxyamphetamine; Animals; Body Temperature Regulation; Brain; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Female; Fever; Humans; Hydroxyindoleacetic Acid; Male; Mixed Function Oxygenases; N-Methyl-3,4-methylenedioxyamphetamine; Paroxetine; Phenotype; Proadifen; Quinidine; Rats; Rectum; Serotonin; Serotonin Agents; Sex Factors; Tritium
PubMed: 7582557
DOI: 10.1111/j.1476-5381.1995.tb15037.x -
BMC Medical Genetics Mar 2012There are no known causes for progressive supranuclear palsy (PSP). The microtubule associated protein tau (MAPT) H1 haplotype is the major genetic factor associated...
BACKGROUND
There are no known causes for progressive supranuclear palsy (PSP). The microtubule associated protein tau (MAPT) H1 haplotype is the major genetic factor associated with risk of PSP, with both oxidative stress and mitochondrial dysfunction also implicated. We investigated whether specific single nucleotide polymorphisms (SNPs) in genes encoding enzymes of xenobiotic detoxification, mitochondrial functioning, or oxidative stress response, including debrisoquine 4-hydroxylase, paraoxonase 1 and 2, N-acetyltransferase 1 and 2 (NAT2), superoxide dismutase 1 and 2, and PTEN-induced putative kinase are associated with PSP.
METHODS
DNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 ± 8 years; age at death 75 ± 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 ± 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay.
RESULTS
The proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001).
CONCLUSIONS
Our results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP.
Topics: Aged; Aged, 80 and over; Arylamine N-Acetyltransferase; Aryldialkylphosphatase; Case-Control Studies; Cytochrome P-450 CYP2D6; Female; Genetic Predisposition to Disease; Humans; Inactivation, Metabolic; Isoenzymes; Male; Middle Aged; Mitochondria; Oxidative Stress; Polymorphism, Single Nucleotide; Protein Kinases; Superoxide Dismutase; Superoxide Dismutase-1; Supranuclear Palsy, Progressive; tau Proteins
PubMed: 22424094
DOI: 10.1186/1471-2350-13-16 -
British Journal of Clinical Pharmacology Jan 1978The urinary recovery and plasma concentration of debrisoquine (D) and its metabolite 4-hydroxydebrisoquine (HD) has been studied following single and multiple oral...
The urinary recovery and plasma concentration of debrisoquine (D) and its metabolite 4-hydroxydebrisoquine (HD) has been studied following single and multiple oral administration of debrisoquine hemisulphate to 15 hypertensive in-patients and four normal volunteers. Incremental doses and prolonged administration led to a proportionately greater urinary recovery and higher plasma concentration of D but the proportion recovered as HD fell while its plasma concentration remained unchanged. Dividing a dose or administering a single oral dose of D resulted in the formation of proportionately more HD and a lower urinary recovery of D. These findings suggest that the metabolism of D to HD may be partially saturated or inhibited by D itself or by HD. Peak urinary excretion rates and plasma concentrations of both D and HD occurred 2 h after a single dose suggesting rapid absorption and presystemic metabolism. HD was eliminated more rapidly than D. Mean (± s.d.) elimination half-life from the urine for HD was 9.6 ± 3.7 h and for D was 16.2 ± 5.7 h. Reasons for this are discussed. Renal clearance of D and HD was not constant. A fall was observed with time after a single dose but on multiple dosing the clearance fell with increasing plasma concentrations. Mean (± s.d.) renal clearance values during multiple administration were D 282 ± 88 ml/min and HD 371 ± 178 ml/min. It is suggested that active saturable tubular secretion of D and HD may be responsible for their renal elimination. The distribution of D in the blood was studied after a single dose to one volunteer. The greatest concentration of the drug was in the platelet rich fraction from which it was eliminated slowly. The elimination half-lives in plasma and platelet rich plasma were 17.5 h and 56 h respectively. On early multiple dosing the hypotensive response was related to high plasma D concentrations.
Topics: Adult; Blood Pressure; Debrisoquin; Drug Administration Schedule; Food; Humans; Hypertension; Isoquinolines; Kidney; Kinetics; Male
PubMed: 619932
DOI: 10.1111/j.1365-2125.1978.tb01594.x -
Anticancer Research 2004Carcinogenesis of the prostate involves androgen influences, and associations between genetic polymorphisms of androgen receptor and metabolizing enzymes and prostate...
Carcinogenesis of the prostate involves androgen influences, and associations between genetic polymorphisms of androgen receptor and metabolizing enzymes and prostate cancer risk have been reported. Roles for non-androgenic hormones are not well defined, but they also may have an impact judging from epidemiological and animal experimental alphalambda zeta of data. The purpose of the study was to determine whether hormone-related polymorphisms are associated with prostate cancer risk. A case-control study was performed with 147 Japanese prostate cancer patients and 266 urological controls. Polymorphisms of target genes [cytochrome P450 (CYP) 1B1, Leu432Val; debrisoquine hydroxylase, (CYP2D6)*4; aromatase (CYP19), Arg264Cys; estrogen receptor (ER)alpha-Xx (Xba I) and Pp (Pvu II); ERbeta-Rr (Rsa I); progesterone receptor (PR) Alu in intron 7] were examined by PCR-based methods. The capital and small letters signify the absence and presence of restriction sites, respectively. Odds ratios (OR) were adjusted for age using multiple logistic regression analysis with SPSS Medical Pack. Among the seven examined genetic polymorphisms, significant associations between CYP1B1 Leu432Val (OR 4.80; 95% confidence interval (CI), 1.21-19.05) and Alu in intron 7 of PR (OR 4.17; 95%CI, 1.26-13.85) were found. As for combined effects, the CYP1B1 polymorphisms (Leu/Val+Val/Val) together with heterozygosity for Alu in the PR were more frequent among prostate cancer patients (1.45%) than controls (0.41%), although without significance (OR, 3.99; 95%CI, 0.36-44.8). The combination of ERalpha (P/p+p/p) polymorphisms with heterozygosity for Alu in the PR demonstrated an OR of 4.56 (95%CI, 1.01-20.6). This pilot study showed that CYP1B1 and PR polymorphisms, alone or in combination, might be associated with prostate cancer risk. They might, therefore, have potential as a tool for identifying high-risk individuals.
Topics: Adenocarcinoma; Alleles; Case-Control Studies; Cytochrome P-450 Enzyme System; Genetic Predisposition to Disease; Genotype; Humans; Isoenzymes; Japan; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Prostatic Neoplasms; Receptors, Estrogen; Receptors, Progesterone
PubMed: 15330195
DOI: No ID Found -
British Journal of Clinical Pharmacology Dec 19961. Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia. 2. Nicergoline is rapidly... (Clinical Trial)
Clinical Trial
1. Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia. 2. Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-alpha-methoxy-9,10-dihydrolysergol (MMDL), which is further N-demethylated to form 10-alpha-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms. 3. After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes. 4. The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL Cmax 59 nmol l-1 and AUC (0, th) 144 nmol l-1h, mean MDL Cmax 183 nmol l-1 and AUC 2627 nmol l-1h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL Cmax 356 nmol l-1 and AUC 10512 nmol l-1h, MDL concentrations below limit of quantitation). 5. We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.
Topics: Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Biotransformation; Blood Pressure; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Debrisoquin; Female; Half-Life; Heart Rate; Humans; Male; Mephenytoin; Mixed Function Oxygenases; Nicergoline; Phenotype; Vasodilator Agents
PubMed: 8971425
DOI: 10.1046/j.1365-2125.1996.00471.x -
British Journal of Clinical Pharmacology Feb 2013Pegylated interferon-based therapy is recommended for treatment of hepatitis C virus (HCV) infection. Because interferons are known to down-regulate hepatic cytochrome...
AIM
Pegylated interferon-based therapy is recommended for treatment of hepatitis C virus (HCV) infection. Because interferons are known to down-regulate hepatic cytochrome P450 (CYP) enzymes, which are involved in drug metabolism and clearance, there is a need to investigate the effect of peginterferon (PEG-IFN) alfa-2a (40KD) on the activity of these enzymes in vivo.
METHODS
Fourteen healthy, male volunteers aged 18 to 45 years were recruited into an open label, two period, single centre study in which CYP enzyme activity was measured by administration of the selectively metabolized probe drugs theophylline (CYP1A2), tolbutamide (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6) and dapsone (CYP3A4) on day 1 of the study. PEG-IFN alfa-2a (40KD) 180 μg was given subcutaneously each week from day 15 to 36, and probe drugs were re-administered on day 37. Probe drugs and metabolites were quantified in plasma or urine samples and used to derive pharmacokinetic parameters.
RESULTS
PEG-IFN alfa-2a (40KD) significantly increased the area under the serum drug concentration vs. time curve (AUC(0,∞)) for theophylline by 24%, with a reduction in the mean oral clearance of theophylline of 20%. There were no effects on the pharmacokinetics of any of the other probe drugs. The incidence of adverse events was as expected in subjects receiving pegylated interferon.
CONCLUSION
These results suggest there may be an inhibitory effect of PEG-IFN alfa-2a (40KD) on CYP1A2. PEG-IFN alfa-2a (40KD) had no effect on CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in healthy subjects.
Topics: Adolescent; Adult; Antiviral Agents; Area Under Curve; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Humans; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Young Adult
PubMed: 22765278
DOI: 10.1111/j.1365-2125.2012.04373.x -
British Journal of Clinical Pharmacology Oct 1999To investigate the pharmacokinetics and safety of tolterodine and tolterodine metabolites after single-and multiple-dose administration in the absence and presence of... (Clinical Trial)
Clinical Trial Comparative Study
AIMS
To investigate the pharmacokinetics and safety of tolterodine and tolterodine metabolites after single-and multiple-dose administration in the absence and presence of ketoconazole, an inhibitor of cytochrome P450 (CYP) 3A4, in healthy volunteers with deficient CYP2D6 activity, i.e. poor metabolisers of debrisoquine.
METHODS
Eight healthy volunteers received single oral doses (2 mg) of tolterodine l-tartrate. Following a wash-out period of about 3 months, six of the subjects participated in a multiple-dose (1 mg twice daily) phase of the study. Ketoconazole 200 mg was given once daily for 4-4.5 days during both the single and multiple dose tolterodine administration phases. Blood samples were drawn and the pharmacokinetics of tolterodine and its metabolites were determined.
RESULTS
A decrease (P<0.01) in apparent oral clearance of tolterodine, from 10- 12 l h-1 to 4.3-4.7 l h-1, was obtained during concomitant administration of ketoconazole, yielding at least a two-fold increase in the area under the serum concentration-time curve after single as well as after multiple doses following single dose administration of tolterodine. The mean (+/-s.d.) terminal half-life increased by 50% from 9.7+/-2.7 h to 15+/-5.4 h in the presence of ketoconazole.
CONCLUSIONS
CYP3A4 is the major enzyme involved in the elimination of tolterodine in individuals with deficient CYP2D6 activity (poor metabolisers), since oral clearance of tolterodine decreased by 60% during ketoconazole coadministration. This inhibition resulted in 2.1-fold increase in AUC.
Topics: Adult; Antifungal Agents; Benzhydryl Compounds; Cresols; Cross-Over Studies; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Female; Humans; Ketoconazole; Male; Mixed Function Oxygenases; Muscarinic Antagonists; Phenotype; Phenylpropanolamine; Time Factors; Tolterodine Tartrate
PubMed: 10583027
DOI: 10.1046/j.1365-2125.1999.00053.x -
Clinical Pharmacology and Therapeutics May 1994Phenotypic trait values in 166 healthy white subjects (age range, 18 to 88 years) were determined for dapsone N-hydroxylation, dapsone N-acetylation, debrisoquin...
Phenotypic trait values in 166 healthy white subjects (age range, 18 to 88 years) were determined for dapsone N-hydroxylation, dapsone N-acetylation, debrisoquin 4-hydroxylation, and S-mephenytoin 4'-hydroxylation after single oral dose administration of the probe drugs dapsone (100 mg), debrisoquin (10 mg), and mephenytoin (100 mg). No associations or evidence of cosegregation were found between the individual routes of metabolism. Dapsone N-hydroxylation exhibited a unimodal distribution, with marked (tenfold) intersubject variability, and aging was associated with reduced N-oxidation. However, the other measured routes of metabolism were age independent, but intersubject variability in all of the trait measurements increased with age. In subjects younger than 50 years, S-mephenytoin 4'-hydroxylation was modestly (34%) less in men than in women. In contrast, dapsone N-acetylation, dapsone N-hydroxylation, and debrisoquin 4-hydroxylation were not influenced by gender. Previous smoking habit and alcohol consumption were not associated with a difference in any of the four routes of metabolism. Accordingly, the measured phenotypic traits of drug oxidation and N-acetylation appear to be quite robust in regard to some common demographic variabilities present in population studies, with the exception of dapsone N-hydroxylase, which is affected by aging.
Topics: Acetylation; Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dapsone; Debrisoquin; Female; Humans; Hydroxylation; Male; Mephenytoin; Middle Aged; Mixed Function Oxygenases; Phenotype; Regression Analysis; White People
PubMed: 8181193
DOI: 10.1038/clpt.1994.62 -
Kidney International Nov 1985Various blood pressure (BP)-regulating factors were assessed before and after 4 weeks of selective norepinephrine (NE) inhibition with the sympathetic neurone blocker,...
UNLABELLED
Various blood pressure (BP)-regulating factors were assessed before and after 4 weeks of selective norepinephrine (NE) inhibition with the sympathetic neurone blocker, debrisoquine, in nine hypertensive, nine normotensive hemodialysis patients (HDP), and 11 normal subjects. On placebo, hypertensive HDP had an increased total blood volume (P less than 0.05) and exchangeable sodium (P less than 0.001), while both HDP groups had increased (P less than 0.05) plasma clearances of NE and angiotensin II (AII), and tended to have higher basal plasma NE, renin, and AII levels, and lower BP responses to NE or AII than normal subjects. Plasma epinephrine and the chronotropic dose of isoproterenol (CDI) did not differ significantly among groups. Debrisoquine lowered supine BP markedly in hypertensive HDP (on average from 181/107 to 148/88 mm Hg) and slightly in normotensive HDP (143/78 to 131/76 mm Hg), but not in normal subjects (116/74 to 120/79 mm Hg). In all groups, plasma NE, CDI, and NE pressor dose were reduced in parallel (by 35 to 75%; P less than 0.05 to less than 0.001), and the relation between stepwise increasing plasma NE and BP changes during NE infusion was commensurably displaced to the left (P less than 0.01). The remaining parameters were not changed consistently.
CONCLUSION
HDP, as normal subjects, respond to decreased sympathetic outflow with increased alpha- and beta-receptor sensitivity. Hypertension in HDP depends strongly on a NE-related mechanism. The latter seems to complement renin-angiotensin, sodium and fluid volume in the pathogenesis of high BP.
Topics: Adult; Aged; Angiotensin II; Blood Pressure; Blood Volume; Debrisoquin; Female; Heart Rate; Humans; Hypertension; Isoproterenol; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Renal Dialysis
PubMed: 4087696
DOI: 10.1038/ki.1985.203 -
Yakugaku Zasshi : Journal of the... Jan 2007The effects of cyclosporine and tacrolimus on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation,...
The effects of cyclosporine and tacrolimus on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6beta-hydroxylation activities in human liver microsomes were compared. Cyclosporine and tacrolimus, at concentrations of 0.2 or 2 muM, neither inhibited nor stimulated any of the metabolic activities except for those of CYP3A4. On the other hand, cyclosporine and tacrolimus competitively inhibited CYP3A4-mediated nifedipine oxidation activity, with inhibition constants (K(i)) of 1.42 and 0.36 muM, respectively. In addition, 20 muM cyclosporine inhibited CYP2C19 and CYP2D6 activities by 29% and 30%, respectively. These results suggest that tacrolimus would not cause clinically significant interactions with other drugs, which are metabolized by CYPs, via the inhibition of hepatic metabolism and that the reason why cyclosporine, but not tacrolimus, has a pharmacokinetic inhibitory effect might be that the dosage and/or the unbound concentrations around its metabolic enzymes are higher than those of tacrolimus, rather than the differences in the inhibition potential. Obvious substrate-dependent effects on CYP3A4-inhibition potential were not observed.
Topics: Cells, Cultured; Cyclosporine; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Humans; Microsomes, Liver; Tacrolimus
PubMed: 17202802
DOI: 10.1248/yakushi.127.209