In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone.
ABSTRACT The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures.
The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone.
The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59).
These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.
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ABSTRACT: The aim of this study was to investigate cytochrome P4503A activity and its correlation with the development of osternecrosis (ON) among male and female steroid-treated rabbits. Forty adult rabbits (male, n = 20; female, n = 20) were injected once with 20 mg/kg of methylprednisolone intramuscularly. Haematologically, cytochrome P4503A activity was measured by plasma 1'-hydroxymidazolam-to-midazolam (1'-OH-MDZ/MDZ) ratio just before and 48 h after the steroid injection. We also measured the levels of oestradiol every week. Both femora and humeri were histopathologically examined for the presence of ON. Fifteen of 20 male rabbits (75%) developed ON, while 6 of 20 female rabbits (30%) did so. There was a significant difference in the rate of incidence of ON between male and female rabbits (P = 0.010). The 1'-OH-MDZ/MDZ ratio in female rabbits just before, as well as 48 h after the steroid injection was significantly higher than that in male rabbits (P = 0.039 and P = 0.001 respectively). In addition, 1'-OH-MDZ/MDZ ratio in female rabbits significantly increased in 48 h after the steroid injection (P = 0.044), while that in male rabbits did not so (P = 0.978). The levels of oestradiol in female rabbits were significantly higher than those in male rabbits during the experimental period (P = 0.008). In conclusion, this study indicates that the gender difference in cytochrome P4503A activity may be one of the important factors for the development of steroid-induced ON, possibly due to the effects of oestradiol.International Journal of Experimental Pathology 10/2013; DOI:10.1111/iep.12060 · 2.05 Impact Factor
Article: Functional gene variants of CYP3A4.[Show abstract] [Hide abstract]
ABSTRACT: Cytochrome P450 3A (CYP3A4) is involved in the metabolism of more drugs in clinical use than any other foreign compound metabolizing enzyme in humans. Recently, there is increasing evidence that variants in the CYP3A4 gene have functional significance and - in rare cases - lead to loss of activity implying tremendous consequences for the patients. This review article highlights the functional consequences all CYP3A4 variants, recognized by the Human Cytochrome P450 (CYP) Allele Nomenclature Database.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 13 June 2014; doi:10.1038/clpt.2014.129.Clinical Pharmacology & Therapeutics 06/2014; 96(3). DOI:10.1038/clpt.2014.129 · 7.39 Impact Factor
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ABSTRACT: Tacrolimus (TAC) is one of the most successful immunosuppressive drugs in transplantation. Its pharmacokinetics (PK) and pharmacogenetics (PG) have been extensively studied, with many studies showing the influence of CYP3A5 on tacrolimus metabolism and bioavailability. However, data concerning the functional significance of ABCB1 polymorphisms are uncertain due to inconsistent results. We evaluated the association between ABCB1 diplotypes, CYP3A5 polymorphisms and tacrolimus disposition in a cohort of Brazilian transplant recipients. Individuals were genotyped for the CYP3A5*3 allele and ABCB1 polymorphisms (2677G>A/T, 1236C>T, 3435C/T) using a TaqMan(®) PCR technique. Diplotypes were analysed for correlation with the TAC dose-normalised ratio (Co/dose). We genotyped 108 Brazilian kidney recipients for CYP3A5 (11% CYP3A5*1/*1; 31% CYP3A5*1/*3 and 58% CYP3A5*3/*3) and ABCB1 haplotypes (42% CGC/CGC; 41% GCG/TTT and 17% TTT/TTT). Homozygous subjects for the CYP3A5*3 allele or carriers of the ABCB1 TTT/TTT diplotype showed a higher Co/dose ratio compared to wild type subjects [130.2 (97.5-175.4) vs. 71.3 (45.6-109.0), p<0.0001 and 151.8 (112.1-205.6) vs. 109.6 (58.1-132.9), p=0.01, respectively]. When stratified for the CYP3A5*3 group, ABCB1 TTT/TTT individuals showed a higher Co/dose ratio compared to non-TTT/TTT individuals [167.8 (130.4-218.0) vs. 119.4 (100.2-166.3), p=0.04]. Multivariate linear regression analysis showed that the effects of CYP3A5 polymorphisms and ABCB1 diplotypes remained significant after correction for confounding factors. CYP3A5 is the major enzyme responsible for the marked interindividual variability in TAC pharmacokinetics, but it cannot be considered alone when predicting dose adjustment because ABCB1 diplotypes also affect tacrolimus disposition, showing independent and additive effects on the TAC dose-normalised concentration.British Journal of Clinical Pharmacology 02/2014; 78(2). DOI:10.1111/bcp.12345 · 3.69 Impact Factor