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CYP2D6 Activity (cyp2d6 + activity)
Selected AbstractsCYP2D6 gene deletion allele in patients with neuroleptic malignant syndrome: Preliminary reportPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 4 2005DAIJI KATO md Abstract, Neuroleptic malignant syndrome (NMS) is a potentially fatal adverse reaction to psychopharmacologic treatment. Reported herein are two NMS patients with schizophrenia who were found to possess a CYP2D6 gene deletion allele (CYP2D6*5). The deletion results in decreased CYP2D6 activity, possibly leading to drug accumulation. Both patients with NMS had been treated with neuroleptics, including CYP2D6 substrates. Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analyses and long PCR were performed to detect CYP2D6 genotype. One patient was found to possess *5/*10; the other had a *1/*5 genotype. The present preliminary report suggests that pharmacokinetic factors cannot be excluded and the CYP2D6 polymorphism is possibly associated with the etiology of NMS. [source] The in vitro Inhibitory Potential of Trade Herbal Products on Human CYP2D6-Mediated Metabolism and the Influence of EthanolBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2007Bent H. Hellum Herbal components were extracted from commercially available products in a way that ensured the same composition of constituents in the extract as in the original trade products. c-DNA baculovirus expressed CYP2D6 was used with dextromethorphan as substrate. Quinidine was included as a positive control inhibitor. A validated high performance liquid chromatography methodology was used to quantify the formation of dextrorphan (product of dextromethorphan O-demethylation). Ethanol showed a biphasic effect on CYP2D6 metabolism, increasing initially the CYP2D6 activity with 175% of control up to a concentration of 1.1%, where after ethanol linearly inhibited the CYP2D6 activity. All the investigated herbs inhibited CYP2D6 activity to some extent, but only St. John's wort, common sage and common valerian were considered possible candidates for in vivo clinically significant effects. They showed IC50 values of 0.07 ± 7 × 10,3 mg/ml, 0.8 ± 0.05 mg/ml and 1.6 ± 0.2 mg/ml, respectively. St. John's wort inhibited CYP2D6-mediated metabolism in an uncompetitive manner, while common valerian and common sage in a non-competitive manner demonstrated interherb differences in inhibition patterns and differences when compared to the more homogenous competitive inhibitor quinidine. Common valerian was the only herb that showed a mechanistic inhibition of CYP2D6 activity and attention should be paid to a possible toxicity of this herb. [source] Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2000L.H. Cohen Abstract Six 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (the present cholesterol-lowering drugs known as statins), lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), atorvastatin (A) and cerivastatin (C) are shown to be potent inhibitors of cholesterol synthesis in human hepatocytes, the target tissue for these drugs in man. All six inhibited in the nM range (IC50 values: 0.2,8.0 nM). As daily used cholesterol-lowering drugs they are likely coadministered with other drugs. While several cytochrome P450 (CYP) enzymes are involved in drug metabolism in the liver and thus play an important role in drug,drug interaction it was investigated which of these enzymes are influenced by the active forms of the six statins. These enzyme activities were studied in human liver microsomal preparations, and in simian and human hepatocytes in primary culture. The following CYP reactions were used: nifedipine aromatization (CYP3A4), testosterone 6,-hydroxylation (CYP3A4), tolbutamide methylhydroxylation (CYP2C9), S -mephenytoin 4-hydroxylation (CYP2C19), bufuralol 1,-hydroxylation (CYP2D6), aniline 4-hydroxylation (CYP2E1), coumarin 7-hydroxylation (CYP2A6) and 7-ethoxyresorufin O -dealkylation (CYP1A1/2). In the human liver microsomes the statins (concentrations up to 400 µM) did not influence the CYP1A1/2 activity and hardly the CYP2A6 and CYP2E1 activities. Except P, the other five statins were stronger inhibitors of the CYP2C19 activity with IC50 values around 200 µM and the same holds for the effect of A, C and F on the CYP2D6 activity. L and S were weaker inhibitors of the latter enzyme activity, whereas P did not influence both activities. About the same was observed for the statin effect on CYP2C9 activity, except that F was a strong inhibitor of this activity (IC50 value: 4 µM). Using the assay of testosterone 6,-hydroxylation the CYP3A4 activity was decreased by L, S and F with IC50 values of about 200 µM and a little more by C and A (IC50 around 100 µM). P had hardly an effect on this activity. To a somewhat less extent the same trend was seen when CYP3A4 activity was measured using nifedipine as substrate. The inhibitory effects observed in microsomes were verified in suspension culture of freshly isolated hepatocytes from Cynomolgus monkey (as a readily available model) and of human hepatocytes. In general the same trends were seen as in the human microsomes, except that in some cases the inhibition of the CYP activity was less, possibly by the induction of the particular CYP enzyme by incubation of the cells with a particular statin. F remained a strong inhibitor of CYP2C9 activity in human and monkey hepatocytes. A induced the CYP2C9 in monkey hepatocytes but was an inhibitor of the CYP2C9 in human hepatocytes. A, S, L and C were moderate inhibitors in both cellular systems of CYP3A4. P was not affecting any of the CYP activities in the three systems studied. It is concluded that different CYP enzymes interact with different statins and therefore differences in between these drugs are to be expected when drug,drug interaction is considered. Copyright © 2000 John Wiley & Sons, Ltd. [source] The CYP2D6 polymorphism in relation to the metabolism of amitriptyline and nortriptyline in the Faroese populationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008Jónrit Halling WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ,,The metabolisms of amitriptyline (AT) to (E)-10-hydroxyamitriptyline and of nortripyline (NT) to (E)-10-hydroxynortriptyline are catalysed by CYP2D6. ,,A correlation between the sparteine metabolic ratio and the NT/(E)-10-hydroxynortriptyline and the AT/(E)-10-hydroxyamitriptyline ratios, respectively, has been observed in patients in treatment with the same dose of AT or NT. ,,The frequency of CYP2D6 poor metabolizers (PMs) is 15% (twofold compared with other Whites) among healthy Faroese. ,,This frequency has not been investigated in Faroese patients in AT treatment and the consequences of the CYP2D6 PM phenotype for dose and plasma concentrations of AT and metabolites are not known in these patients. WHAT THIS STUDY ADDS ,,In patients treated with different daily dosages (5,100 mg) of AT a correlation between the sparteine metabolic ratio and the NT/(E)-10-hydroxynortriptyline and AT/(E)-10-hydroxyamitriptyline ratios was observed. ,,A high proportion (22%) of CYP2D6 PMs in a Faroese patient group medicated with AT was observed. ,,However, similar doses of AT and concentrations of AT and NT were noted in extensive metabolizers and in PMs. AIM To determine the frequency of CYP2D6 poor metabolizers (PMs) in a Faroese patient group medicated with amitriptyline (AT) and to investigate plasma concentrations of AT and metabolites in relation to CYP2D6. METHODS CYP2D6 phenotype and genotype were determined in 23 Faroese patients treated with AT. Plasma concentrations of AT and metabolites were determined by high-performance liquid chromatography and investigated in relation to CYP2D6 activity. RESULTS Of the 23 patients phenotyped and genotyped, five (22%) (95% confidence interval 7.5, 43.7) were CYP2D6 PMs. No difference was found in AT daily dosage between PMs (median 25 mg day,1; range 5,80) and extensive metabolizers (EMs) (median 27.5 mg day,1; range 10,100). The (E)-10-OH-nortriptyline (NT)/dose concentrations were higher in EMs than in PMs and the NT/(E)-10-OH-NT and AT/(E) -10-OH-AT ratios were higher in PMs compared with EMs. The log sparteine metabolic ratio correlated positively with the NT/(E)- 10-OH-NT ratio (rs = 0.821; P < 0.0005) and the AT/(E)- 10-OH-AT ratio (rs = 0.605; P < 0.006). CONCLUSION A high proportion of CYP2D6 PMs was found in a Faroese patient group medicated with AT. However, similar doses of AT and concentrations of AT and NT were noted in EMs and PMs, probably due to varying doses and indications for AT treatment. [source] Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2001G. P. Pageaux Aims, The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. Methods, The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX® capsules). Results, The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 ± 11.5 h; 17.5 ± 10.2 h (mean ±,s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 ± 200 ng ml ,1h vs 331 ± 282 ng ml ,1h). There was a significant correlation between the AUC(0,,) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. Conclusions, These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity. [source] | ||||||||||