Topic
Nirvanol
About: Nirvanol is a research topic. Over the lifetime, 54 publications have been published within this topic receiving 1862 citations. The topic is also known as: nirvanol.
Papers published on a yearly basis
Papers
Journal Article•
TL;DR: Bupropion hydroxylation is mediated almost exclusively by CYP2B6 and can serve as an index reaction reflecting activity of this isoform and suggest a low inhibitory potency versus CYP 2D6, the clinical importance of which is not established.
Abstract: The in vitro biotransformation of bupropion to hydroxybupropion was studied in human liver microsomes and microsomes containing heterologously expressed human cytochromes P450 (CYP). The mean (±S.E.) K m in four human liver microsomes was 89 (±14) μM. In microsomes containing cDNA-expressed CYPs, hydroxybupropion formation was mediated only by CYP2B6 at 50 μM bupropion ( K m 85 μM). A CYP2B6 inhibitory antibody produced more than 95% inhibition of bupropion hydroxylation in four human livers. Bupropion hydroxylation activity at 250 μM was highly correlated with S -mephenytoin N- demethylation activity (yielding nirvanol), another CYP2B6-mediated reaction, in a panel of 32 human livers ( r = 0.94). The CYP2B6 content of 12 human livers highly correlated with bupropion hydroxylation activity ( r = 0.96). Thus bupropion hydroxylation is mediated almost exclusively by CYP2B6 and can serve as an index reaction reflecting activity of this isoform. IC 50 values for inhibition of a CYP2D6 index reaction (dextromethorphan O -demethylation) by bupropion and hydroxybupropion were 58 and 74 μM, respectively. This suggests a low inhibitory potency versus CYP2D6, the clinical importance of which is not established. Since bupropion is frequently coadministered with other antidepressants, IC 50 values (μM) for inhibition of bupropion hydroxylation were determined as follows: paroxetine (1.6), fluvoxamine (6.1), sertraline (3.2), desmethylsertraline (19.9), fluoxetine (59.5), norfluoxetine (4.2), and nefazodone (25.4). Bupropion hydroxylation was only weakly inhibited by venlafaxine, O -desmethylvenlafaxine, citalopram, and desmethylcitalopram. The inhibition of bupropion hydroxylation in vitro by a number of newer antidepressants suggests the potential for clinical drug interactions.
405 citations
Journal Article•
TL;DR: The highly specific MAb 49-10-20 was used to provide further confirmation that S-mephenytoin N-demethylation to nirvanol is a CYP2B6 selective probe and some, but not all substrates of CYP1B6 demonstrate autoactivation.
Abstract: Previous studies in this laboratory have determined the lack of specificity of several antibody and substrate probes of CYP2B6. The goals of the current study were to examine the expression of CYP2B6 in a bank of human liver microsome (HLM) samples using a new specific monoclonal antibody (MAb 49-10-20) and to further characterize the substrate specificity of CYP2B6. A 100-fold variability in expression of immunodetectable CYP2B6 was demonstrated in a bank of 19 HLM samples (0.7 pmol/mg protein to 71.1 pmol/mg protein) using MAb 49-10-20. CYP2B6 levels were found to significantly (P < .0001) correlate with S-mephenytoin N -demethylation to nirvanol (r2 = 0.89), 7-hydroxy-4-trifluoromethylcoumarin formation (r2 = 0.81) and several markers of CYP3A levels and activity. The relationships between nirvanol formation and CYP3A levels or activity were found to depend on two HLM samples. K m (apparent) values were generated for benzyloxyresorufin O -deethylation (1.3 μM), benzphetamine N -demethylation (93.4 μM), 3-cyano 7-ethoxycoumarin O -deethylation (71.3 μM), midazolam 1′-hydroxylation (46.1 μM) and 4-chloromethyl-7-ethoxycoumarin O -deethylation (33.7 μM) using expressed CYP2B6. Testosterone 16β-hydroxylation by expressed CYP2B6 resulted in atypical kinetics characteristic of substrate activation. The data best fit the Hill equation with a K m (apparent) of 50.5 μM and an n of 1.3 ( n = number of sites bound by activator). In conclusion, the highly specific MAb 49-10-20 was used to provide further confirmation that S -mephenytoin N -demethylation to nirvanol is a CYP2B6 selective probe. Finally, some, but not all substrates of CYP2B6 demonstrate autoactivation.
184 citations
TL;DR: The dependence of both metabolic relations on NADPH and the inhibition by CO suggest that they are mediated by cytochrome P-450-type monooxygenases, which provides a mechanistic explanation for the stereospecific pharmacokinetics in vivo.
75 citations
Journal Article•
TL;DR: The N-demethylation of (S)-MP to nirvanol may be a useful means of probing the activity of CYP2B6 in vitro when concentrations of >1000 microM are used, but it is unlikely to be a suitable phenotyping tool for this isoform in vivo, where concentrations of>1000 micro M are rarely encountered.
Abstract: We tested the ability of human liver microsomes (HLMs) and recombinant human cytochrome P450 (CYP or P450) isoforms to catalyze the N-demethylation of nirvanol-free (S)-mephenytoin [(S)-MP] in vitro. In mixed HLMs, the kinetics of (S)-MPN-demethylation suggested two contributing activities. A high-affinity/low-capacity component exhibited aKM of 174.1 μM and aVmax of 170.5 pmol/mg protein/min, whereas a low-affinity/high-capacity component exhibited aKM of 1911 μM and aVmax of 3984 pmol/mg protein/min. The activity of the high-affinity component was completely abolished by sulfaphenazole, with little effect on the low-affinity component. Of the recombinant P450 isoforms tested, only CYP2B6 and CYP2C9 formed nirvanol from (S)-MP. The KMvalue (150 ± 42 μM) derived for recombinant CYP2C9 was close to that obtained for the high-affinity/low-capacity component in mixed HLMs (KM = 174.1 μM). The predicted contribution of this activity at concentrations (1–25 μM) achieved after a single 100-mg dose of racemic MP is approximately 30% of the rate of nirvanol formation. At concentrations of >1000 μM, we estimate that >90% of the rate can be explained by the low-affinity activity (CYP2B6). Therefore, the N-demethylation of (S)-MP to nirvanol may be a useful means of probing the activity of CYP2B6 in vitro when concentrations of >1000 μM are used, but it is unlikely to be a suitable phenotyping tool for this isoform in vivo, where concentrations of >1000 μM are rarely encountered.
61 citations
TL;DR: The M‐defection occurs among Canadian Caucasians with a frequency of 2% (0.0% to 7.5% with a confidence limit of 99%) and is independent of the S‐defect.
Abstract: The frequency of genetically deficient hydroxylation of mephenytoin (M-defect) was studied in 83 healthy Caucasians living in Toronto The M-defect was compared with the widely studied genetic polymorphism of sparteine/debrisoquine oxidations (S-defect) After ingestion of mephenytoin and sparteine, urine samples (0 to 24 hr) were analyzed for p(4')-hydroxymephenytoin and urine samples over 0 to 12 hr were analyzed for sparteine and 2-and 5-dehydrosparteine by gas chromatographic methods Nirvanol, the N-demethylation product of mephenytoin, was determined by a newly developed gas chromatographic/mass spectrometric method Frequency distributions of both p-hydroxymephenytoin and dehydrosparteine excreted in urine were discontinuous (bimodal), while nirvanol and sparteine data were normally distributed Two poor metabolizers of mephenytoin excreted 2% to 3% of the dose as p-hydroxymephenytoin and excreted normal amounts of nirvanol, but they were extensive metabolizers of sparteine Six poor metabolizers of sparteine were found to be extensive metabolizers of mephenytoin (34% to 42% excreted in urine as p-hydroxyme-phenytoin) Thus the M-defect occurs among Canadian Caucasians with a frequency of 2% (00% to 75% with a confidence limit of 99%) and is independent of the S-defect
56 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2020 | 1 |
| 2011 | 1 |
| 2008 | 1 |
| 2004 | 2 |
| 2003 | 1 |
| 2002 | 1 |