Assessment of Cytochrome P450 Metabolic Clearance Using Hepatocyte Suspension

Abstract Transdermal fentanyl is widely used to control pain in cancer patients. The high pharmacokinetic variability of fentanyl is assumed to be due to cytochrome P450 3A-mediated (CYP3A) N-dealkylation to norfentanyl in humans. However, recently published clinical studies question the importance of the described metabolic pathway. In this small study in palliative cancer patients under real-life clinical conditions, the influence of CYP3A on fentanyl variability was investigated. In addition to the determination of midazolam plasma concentration to reveal CYP3A activity, plasma concentrations of fentanyl and its metabolite, norfentanyl, were measured in identical blood samples of 20 patients who participated in an ongoing trial and had been on transdermal fentanyl. Fentanyl, norfentanyl, midazolam, and 1′-OH-midazolam were quantified by liquid chromatography/tandem mass spectrometry. Plasma concentrations of fentanyl and norfentanyl exhibited a large variability. Mean estimated total clearance of fentanyl and mean metabolic clearance of midazolam (as a marker of CYP3A activity) were 75.5 and 36.3 L/h. Both clearances showed a weak correlation and hence a minimal influence of CYP3A on fentanyl elimination.

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Hepatic Metabolic Clearance of Midazolam, a Cytochrome P450 3A Substrate, in the Presence of Ketoconazole in Rats

Pharmacy and Pharmacology Communications ◽

10.1211/146080899128735207 ◽

1999 ◽

Vol 5 (8) ◽

pp. 529-536 ◽

Cited By ~ 1

Author(s):

F. Higashikawa ◽

T. Murakami ◽

M. Makino ◽

M. Takano

Keyword(s):

Cytochrome P450 ◽

Metabolic Clearance ◽

Cytochrome P450 3A

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Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. III. In Vitro-in Vivo Correlation with Fluconazole

Drug Metabolism and Disposition ◽

10.1124/dmd.107.019000 ◽

2008 ◽

Vol 36 (7) ◽

pp. 1261-1266 ◽

Cited By ~ 20

Author(s):

Chuang Lu ◽

Cicely Berg ◽

Shimoga R. Prakash ◽

Frank W. Lee ◽

Suresh K. Balani

Keyword(s):

Cytochrome P450 ◽

Drug Interactions ◽

Human Hepatocyte ◽

Phenotypic Data ◽

Hepatocyte Suspension ◽

Pharmacokinetic Drug

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Cytochrome P450-2D6 extensive metabolizers are more vulnerable to methamphetamine-associated neurocognitive impairment: Preliminary findings

Journal of the International Neuropsychological Society ◽

10.1017/s1355617710000779 ◽

2010 ◽

Vol 16 (5) ◽

pp. 890-901 ◽

Cited By ~ 30

Author(s):

MARIANA CHERNER ◽

CHAD BOUSMAN ◽

IAN EVERALL ◽

DANIEL BARRON ◽

SCOTT LETENDRE ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Exposure ◽

Neuropsychological Performance ◽

Metabolic Clearance ◽

Extensive Metabolizers ◽

Cytochrome P450 2D6 ◽

Hepatitis C Infection ◽

Similar Drug ◽

Other Substances ◽

P450 2D6

AbstractWhile neuropsychological deficits are evident among methamphetamine (meth) addicts, they are often unrelated to meth exposure parameters such as lifetime consumption and length of abstinence. The notion that some meth users develop neuropsychological impairments while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of meth. One source of differential vulnerability could come from genotypic variability in metabolic clearance of meth, dependent on the activity of cytochrome P450-2D6 (CYP2D6). We compared neuropsychological performance in 52 individuals with a history of meth dependence according with their CYP2D6 phenotype. All were free of HIV or hepatitis C infection and did not meet dependence criteria for other substances. Extensive metabolizers showed worse overall neuropsychological performance and were three times as likely to be cognitively impaired as intermediate/poor metabolizers. Groups did not differ in their demographic or meth use characteristics, nor did they evidence differences in mood disorder or other substance use. This preliminary study is the first to suggest that efficient meth metabolism is associated with worse neurocognitive outcomes in humans, and implicates the products of oxidative metabolism of meth as a possible source of brain injury. (JINS, 2010, 16, 890–901.)

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