Quantitative prediction of hepatic CYP3A activity using endogenous markers in healthy subjects after administration of CYP3A inhibitors or inducers

Lee, J.; Yoon, Seo Hyun; Yi, Sangho; Kim, Andrew Hyoung Jin; Kim, Bora; Lee, Seung Hwan; Yu, Kyung‐Sang; Jang, In Jin; Cho, Joo Youn

doi:10.1016/j.dmpk.2019.04.002

Cited by 15 publications

(10 citation statements)

References 25 publications

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“…While one study found the ratio to be higher in men, 19 another study found the ratio to be higher in women 42 . However, many studies of 6β‐OHC/C have been performed in males only 43–45 …”

Section: Discussionmentioning

confidence: 99%

Studies on CYP3A activity during the menstrual cycle as measured by urinary 6β‐hydroxycortisol/cortisol

Bergström

Lindahl

Warnqvist

et al. 2021

Pharmacology Res & Perspec

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The 6β‐OH‐cortisol/cortisol ratio (6β‐OHC/C) in urine is an endogenous marker of drug‐metabolizing enzyme cytochrome P450 3A (CYP3A). The primary aim of this single center, prospective, non‐interventional cohort study, was to investigate the variability of 6β‐OHC/C during the menstrual cycle. In addition, possible associations between the CYP3A activity and sex hormones, gut microbiota metabolite trimethylamine‐N‐Oxide (TMAO) and microRNA‐27b, respectively, were investigated. Serum and urinary samples from healthy, regularly menstruating women followed for two menstrual cycles were analyzed. Twenty‐six complete menstrual cycles including follicular, ovulatory, and luteal phase were defined based on hormone analyses in serum. 6β‐OHC/C were analyzed in urine and sex hormones, TMAO and miRNA‐27b were analyzed in serum at the same time points. 6β‐OHC/C did not vary between the follicular, ovulatory, or luteal phases. There was a difference in the relative miRNA‐27b expression between the follicular and ovulatory phase ( p = .03). A significant association was found between 6β‐OHC/C and progesterone during the follicular ( p = .005) and ovulatory ( p = .01) phases ( n = 26 for each phase). In addition, a significant association was found between the ratio and TMAO during the ovulatory ( p = .02) and luteal ( p = .002) phases. 6β‐OHC/C and gut microbiota TMAO were significantly associated ( p = .003) when evaluating all values, for all phases ( n = 78). Interestingly, the finding of an association between 6β‐OHC/C in urine and levels of TMAO in serum suggest that gut microbiota may affect CYP3A activity.

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Section: Discussionmentioning

confidence: 99%

Studies on CYP3A activity during the menstrual cycle as measured by urinary 6β‐hydroxycortisol/cortisol

Bergström

Lindahl

Warnqvist

et al. 2021

Pharmacology Res & Perspec

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“…Many metabolites of endogenous compounds are used as markers of the activity of CYP3A enzymes both in vitro and in clinical studies [ 11 , 13 , 222 , 260 , 261 , 262 , 263 , 264 ]. The metabolic ratio of 1β-hydroxydeoxycholic acid to deoxycholic acid in urine has been proposed as a potential endogenous biomarker of CYP3A activities [ 214 ].…”

Section: Involvement Of Cyp3a Enzymes In Biological Processesmentioning

confidence: 99%

The Role of CYP3A in Health and Disease

2022

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CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. CYP3A enzymes are indiscriminate toward substrates and are unique in that these enzymes metabolize both endogenous compounds and diverse xenobiotics (including drugs); almost the only common characteristic of these compounds is lipophilicity and a relatively large molecular weight. CYP3A enzymes are widely expressed in human organs and tissues, and consequences of these enzymes’ activities play a major role both in normal regulation of physiological levels of endogenous compounds and in various pathological conditions. This review addresses these aspects of regulation of CYP3A enzymes under physiological conditions and their involvement in the initiation and progression of diseases.

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“…There is therefore a need for the development of sensitive endogenous biomarkers, especially urinary biomarkers, as an alternative phenotyping method to overcome this challenge. Some endogenous compounds have been demonstrated to have potential as markers that mirror the interindividual variation of enzyme activities in drug metabolism [ 1 , 2 , 3 ]. The identification and validation of such endogenous markers could be useful in the evaluation of new chemical entities for the risk of drug-metabolising enzyme inhibition or induction-based DDI.…”

Section: Introductionmentioning

confidence: 99%

“…There have been encouraging results when CYP3A endogenous biomarkers have been used to capture potential DDIs during early drug development, as well as to guide the design of clinical studies [ 1 ]. Cortisol, cortisone, and dehydroepiandrosterone (DHEA) are extensively metabolised by CYP3A4, with urinary 6β-hydroxycortisol/cortisol and 6β-hydroxycortisone/cortisone ratios being shown to be useful CYP3A activity predictors [ 1 , 9 , 10 , 11 , 12 ]. The plasma concentration of 4β-hydroxycholesterol (4βHC) has also been suggested as a potential endogenous CYP3A biomarker [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug–Drug Interaction in Healthy Volunteers

Thelingwani

Diczfalusy

et al. 2021

JPM

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In this study, we aimed to evaluate the utility of endogenous 1β-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1β-OH-DCA/ToDCA) in spot urine as a surrogate marker of cytochrome P450 3A (CYP3A) activity in the assessment inhibition-based drug–drug interactions in healthy volunteers. This was accomplished through an open-label, three-treatment parallel-arm study in healthy male volunteers from Zimbabwe. Each group received itraconazole (ITZ; 100 mg once daily; n = 10), fluconazole (FKZ; 50 mg once daily; n = 9), or alprazolam (APZ; 1 mg once daily; n = 8) orally. Midazolam (MDZ), dosed orally and intravenously, was used as a comparator to validate the exploratory measures of CYP3A activity and the effects of known inhibitors. Urinary metabolic ratios of 1β-OH-DCA/ToDCA before and after CYP3A inhibitor treatment showed a similar magnitude of inhibitory effects of the three treatments as that measured by oral MDZ clearance. The maximum inhibition effect of a 75% reduction in the 1β-OH-DCA/ToDCA ratio compared to the baseline was achieved in the ITZ group following six once-daily doses of 100 mg. The correlations of the two markers for CYP3A inhibitor treatment were significant (rs = 0.53, p < 0.01). The half-life of urinary endogenous 1β-OH-DCA/ToDCA was estimated as four days. These results suggested that 1β-OH-DCA/ToDCA in spot urine is a promising convenient, non-invasive, sensitive, and relatively quickly responsive endogenous biomarker that can be used for CYP3A inhibition-based drug–drug interaction in clinical studies.

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Quantitative prediction of hepatic CYP3A activity using endogenous markers in healthy subjects after administration of CYP3A inhibitors or inducers

Cited by 15 publications

References 25 publications

Studies on CYP3A activity during the menstrual cycle as measured by urinary 6β‐hydroxycortisol/cortisol

Studies on CYP3A activity during the menstrual cycle as measured by urinary 6β‐hydroxycortisol/cortisol

The Role of CYP3A in Health and Disease

Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug–Drug Interaction in Healthy Volunteers

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