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Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism.

ABSTRACT: Currently, there is considerable debate as to which method is more accurate for measuring the activity of CYP3A in vivo: cortisol 6beta-hydroxylation clearance (Cl(m(6beta))) or the urinary ratio of 6beta-OHF to F (6beta-OHF/F). Furthermore, the value of measuring endogenous levels of cortisol over a 24 h period (AUC(F)) needs to be confirmed. The aim of the present study was to determine which method was most effective at measuring changes in the in vivo activity of CYP3A: AUC(F), Cl(m(6beta)), or 6beta-OHF/F.A two phase, cross-over design was adopted in this study. A total of 24 subjects (12 males and 12 females) were randomly assigned to one of two groups: the test group subjects were given 250 mg clarithromycin tablets twice a day for a period of 4 d, whereas the control group received a placebo twice daily for a similar period. On d 5 of the study, the last dose of either clarithromycin or placebo was supplemented with an oral dose of 7.5 mg midazolam (MDZ); blood and urine samples were then collected at various times. All samples collected at the same sampling times on d 4 were used to evaluate the effects of MDZ administration on cortisol levels and metabolism. The ratio of 1-hydroxymidazolam (1-OHMDZ) concentration to MDZ concentration at 1 h (MR) was taken as a measure of the in vivo CYP3A activity. AUC(F), Cl(m(6beta)), and 6beta-OHF/F were also used as biomarkers for CYP3A activity.No correlations were found (either before or after inhibition) between CYP3A activity and any of the following measures: AUC(F), Cl(m(6beta)), or 6beta-OHF/F (r<0.4, P>0.05). After 4 d of clarithromycin administration, CYP3A activity (MR) decreased by 75% (P=0.000), whereas AUC(F) increased by 19% (P=0.040), and Cl(m(6beta)) and 6beta-OHF/F decreased by 54.2% (P=0.000) and 50% (P=0.003), respectively. No significant changes in AUC(F) (P=0.178), or in the amount of urinary 6beta-OHF (P=0.169), or in F (P=0.391) were found over a 24 h time period, either with or without MDZ administration.Although Cl(m(6beta)) and 6beta-OHF/F can reflect the decline in CYP3A activity, the impression they provide is neither accurate nor complete. AUC(F) is completely ineffective for evaluating variations in CYP3A activity. MDZ administration had no evident effects on either cortisol metabolism or excretion over a period of 24 h.

SUBMITTER: Luo X

PROVIDER: S-EPMC4007188 | biostudies-other | 2009 Sep

REPOSITORIES: biostudies-other

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Project description:Human CYP3A enzymes (including CYP3A4 and CYP4A5) metabolize about 40% of all drugs and numerous other environmental and endogenous substances. CYP3A activity is highly variable within and between humans. As a consequence, therapy with standard doses often results in too low or too high blood and tissue concentrations resulting in therapeutic failure or dose-related adverse reactions. It is an unanswered question how much of the big interindividual variation in CYP3A activity is caused by genetic or by environmental factors. This question can be answered by the twin study approach. Using midazolam as CYP3A probe drug, we studied 43 monozygotic and 14 dizygotic twins and measured midazolam and its metabolite 1-OH-midazolam. In addition, endogenous biomarkers of CYP3A activity, 4ß-OH-cholesterol and 6ß-OH-cortisol, were analyzed. Additive genetic effects accounted for only 15% of the variation in midazolam AUC, whereas 48% was attributed to common environmental factors. In contrast, 73, 56, and 31% of 1-OH-midazolam, 4ß-OH-cholesterol and 6ß-OH-cortisol variation was due to genetic effects. There was a low phenotypic correlation between the four CYP3A biomarkers. Only between midazolam and its 1-OH-metabolite, and between midazolam and 6ß-OH-cortisol we found significant bivariate genetic correlations. Midazolam AUC differed depending on the CYP3A4∗22 variant (p = 0.001) whereas plasma 4ß-OH-cholesterol was significantly lower in homozygous carriers of CYP3A5∗3 (p = 0.02). Apparently, non-genomic factors played a dominant role in the inter-individual variation of the CYP3A probe drug midazolam. A small intra-individual pharmacokinetic variation after repeated administration of midazolam was rated earlier as indication of high heritability of CYP3A activity, but according to present data that could also largely be due to constant environmental factors and/or heritability of liver blood flow. The higher heritabilities of 4ß-OH-cholesterol and of 1-OH-midazolam may deserve further research on the underlying factors beyond CYP3A genes. Clinical Trial Registration: ClinicalTrials.gov: NCT01845194 and EUDRA-CT: 2008-006223-31.

Project description:BACKGROUND:Negative psychological conditions are common in patients with cardiovascular diseases. Although depression has been scrutinized over the years in these patients, only recently has anxiety emerged as another important risk factor. The purpose of this study was to compare the parameters of psychological stress in a population of coronary patients with and without myocardial revascularization procedures and to analyze lifestyle and socio-economic contributors to the state of health of these patients before inclusion in a comprehensive individualized rehabilitation program. METHODS:This study included 500 patients with coronary artery disease (CAD) in stable condition divided in 2 groups: 200 patients who underwent coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) (Group 1) and 300 patients without myocardial revascularization (Group 2) with stable angina or thrombolyzed myocardial infarction. The protocol included screening for anxiety/depression after procedure using three different scales: Duke Anxiety-Depression Scale, Hospital Anxiety and Depression Scale (HADS) and the Type D Personality Scale (DS-14) scale that evaluates negative affectivity (NA) and social inhibition (SI). RESULTS:Significant differences between groups were observed for HAD-A (9.1 ± 4.18 for Group 1 vs. 7.8 ± 4.03 for Group 2, p = 0.002) and DUKE scores (30.2 ± 12.25 for Group 1 vs. 22.7 ± 12.13 for Group 2, p < 0.001). HAD-A scores (p = 0.01) and DUKE scores (p = 0.04) were significantly higher in patients who underwent PTCA vs. CABG. CAD patients without myocardial revascularization (Group 2, n = 300) presented anxiety in proportion of 72.3% (n = 217) out of which 10.7% (n = 32) had severe anxiety, and 180 patients had depression (a proportion of 60%) out of which 1.3% (n = 4) presented severe depression. The correlation between the presence of type 2 diabetes mellitus (T2DM) and type D personality in revascularized patients (n = 200) was significant (Chi2 test, p = 0.010). By applying multinomial regression according to the Cox and Snell R-square model and multivariate linear regression by the Enter method, we demonstrated that male gender, age and marital status proved significant predictors for psychological stress in our study population. CONCLUSIONS:The results obtained in this study provide a framework for monitoring anxiety, depression and type D personality in coronary patients before inclusion in comprehensive rehabilitation programs. Behavioral and psychological stress responses in patients with CAD significantly correlate with risk factors, and could influence the evolution of the disease. Moreover, other factors like gender, income and marital status also seem to play a decisive role. Evaluation of psychological stress parameters contributes to a better individualization at the start of these programs, because it allows adjusting of all potential factors that may influence positive outcomes.

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Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism.

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