The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity

Gorski, J. Christopher; Vannaprasaht, Suda; Hamman, Mitchell A.; Ambrosius, Walter T.; Bruce, Melissa A.; Haehner‐Daniels, Barbara D.; Hall, Stephen D.

doi:10.1016/s0009-9236(03)00187-5

Cited by 188 publications

(170 citation statements)

References 36 publications

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“…MDZ and its metabolites were quantified in serum by liquid chromatography-mass spectrometry using desmethyldiazepam as the internal standard as previously described. 24 The interday coefficient of variation at 1.4, 18, and 50 ng/mL was 9.2%, 6.7%, and 8.9%, respectively. The relative error for quality control samples with nominal values of 1.4, 18, and 50 ng/mL was Ϫ1.0%, 3.3%, and Ϫ2.7%, respectively.…”

Section: Methodsmentioning

confidence: 88%

“…Blood concentrations of MDZ were determined as previously described. 24 The pharmacokinetics of MDZ and CHZ were determined by using noncompartmental methods (Winnonlin v. 4.0, Pharsight Corp, Mountain View, CA). The oral availability of MDZ was calculated by using equation 1:…”

Section: Methodsmentioning

confidence: 99%

“…A sample size of 20 individuals in each group will require a 30% difference in systemic clearance between the groups to have a power of 80% at the .05 significance level, and, based on our studies, this difference was thought to be biologically plausible. 24 A P value less than .05 was considered statistically significant.…”

Section: Methodsmentioning

confidence: 99%

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Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: A comparison with nonalcoholics

et al. 2005

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Alcohol consumption is known to induce hepatic CYP2E1 activity, but its effect on hepatic and intestinal CYP3A in humans is not known. We have conducted a study to compare the CYP2E1 and CYP3A activities in 20 individuals with moderate alcohol consumption and 20 gender-, race-. and body mass index (BMI)-matched nonalcoholics. Intravenous and oral midazolam (MDZ) clearances were used to measure the in vivo CYP3A activity, and chlorzoxazone (CHZ) oral clearance was used to assess in vivo CYP2E1 activity. Furthermore, we assessed the relationship between hepatic CYP2E1 and CYP3A activities and their messenger RNA (mRNA) expression in the peripheral lymphocytes. The systemic clearance (CL) of MDZ was not different between alcoholics (36.9 ؎ 12 L/hr) and nonalcoholics (36.6 ؎ 14.1; P ‫؍‬ .9). The oral availability of MDZ was significantly lower in alcoholics than in the nonalcoholics (0.28 ؎ .09 vs. 0.38 ؎ .17, respectively, P ‫؍‬ .03). The maximum serum concentration after oral midazolam dosing was significantly different between the 2 groups. CHZ CL was significantly higher in alcoholics than in nonalcoholics (31.5 ؎ 11.9 vs. 23.4 ؎ 8.7 L/hr, P < 0.05). CYP3A4 and CYP2E1 mRNA levels were not significantly different between the groups, and no correlation was observed between lymphocyte CYP mRNA and in vivo CYP activity. In conclusion, in individuals with moderate alcohol consumption, there was no alteration in the hepatic CYP3A activity, but the reduced midazolam oral bioavailability suggests that moderate alcohol consumption may cause intestinal CYP3A induction. Lymphocyte CYP2E1 and CYP3A4 mRNA levels did not correlate with CYP2E1 and CYP3A activities. (HEPATOLOGY 2005;41:1144-1150

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Section: Methodsmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

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Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: A comparison with nonalcoholics

et al. 2005

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“…However, the lack of an age effect on these enzymes has also been indicated (Simon et al 2001;Gorski et al 2003;Parkinson et al 2004). Here, we show evidence supporting the impact of age on CYP2C9 activity and a relatively weak genderspecific age effect for CYP1A2, CYP2A6, CYP2B6, CYP2C8, and CYP3A4.…”

Section: Discussionmentioning

confidence: 99%

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Yang¹,

Zhang²,

Molony³

et al. 2010

Genome Res.

236

222

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Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.

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“…Although sex has been noted as determinant of CYP3A4 expression because of twofold higher CYP3A4 levels in female compared with male human liver samples, sex did not affect oral clearance of midazolam, a classical probe for intestinal and hepatic CYP3A, in vivo. 34,35 It may be speculated that plasma levels of budesonide would have been even lower in female healthy volunteers than in male healthy volunteers, further enlarging the difference between patients and healthy volunteers. The finding at baseline is important for physicians treating patients with early-stage PBC.…”

Section: Discussionmentioning

confidence: 99%

No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

et al. 2005

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Induction of cytochrome P450 3A (CYP3A) has been suggested as a mechanism of action of ursodeoxycholic acid (UDCA) in cholestasis. CYP3A is of key importance in human drug metabolism, being involved in presystemic extraction of more than 50% of all drugs currently available and of various endogenous compounds. Therefore, we compared the induction potential of UDCA with that of the prototypical inducer rifampicin in a human model study with the CYP3A substrates budesonide and cortisol. Twelve patients with early-stage primary biliary cirrhosis and eight healthy volunteers were treated with UDCA (15 mg/kg daily) for 3 weeks and subsequently with rifampicin (600 mg/d) for 1 week. Extensive pharmacokinetic profiling of oral budesonide (3 mg) was performed by determination of budesonide and phase I metabolites (6␤-hydroxybudesonide, 16␣-hydroxyprednisolone) in plasma and urine at baseline and at the end of each treatment. In parallel, urinary 6␤-hydroxycortisol, a validated marker of CYP3A induction, was determined. UDCA did not affect biotransformation of budesonide and urinary excretion of 6␤-hydroxycortisol either in patients or in healthy volunteers. Ratios of areas under plasma concentration-time curves (AUC 0-12 h during UDCA/AUC 0-12 h before UDCA) of both metabolites were not higher than those of budesonide itself. In contrast, administration of rifampicin markedly induced CYP3A metabolism, resulting in abolished budesonide plasma levels and high urinary excretion of 6␤-hydroxycortisol. Metabolite formation was enhanced by rifampicin, but not by UDCA (e.g., AUC 16␣-hydroxyprednisolone /AUC budesonide in patients: baseline, 8.6 ؎ 3.9; UDCA, 10.7 ؎ 7.1; rifampicin, 527.0 ؎ 248.7). In conclusion, UDCA is not a relevant inducer of CYP3A enzymes in humans. (HEPATOLOGY 2005;41:595-602.)

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The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity

Cited by 188 publications

References 36 publications

Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: A comparison with nonalcoholics

Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: A comparison with nonalcoholics

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

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