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

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Accurate prediction of cytochrome P450 (CYP) 3A activity in the early stage of drug development and in clinical practice is important. This study aimed to evaluate the previously constructed CYP3A activity prediction model after administration of CYP3A inhibitors and inducers and to modify the model for better prediction of CYP3A activity. Healthy male subjects received the following study drugs during three study periods: midazolam alone (control phase); midazolam with 200 mg of itraconazole (CYP3A inhibition phase); and midazolam with 150 mg of rifampicin (CYP3A induction phase). We quantified the concentrations of several endogenous CYP3A markers in both urine and plasma using gas chromatography-mass spectrometry. The urinary markers, including 6β-hydroxy (OH)-cortisol/cortisol, 6β-OH-cortisone/cortisone, 16α-OH-dehydroepiandrosterone (DHEA)/DHEA, 16α-OH-androstenedione (A-dione)/A-dione and 7β-OH-DHEA/DHEA, were significantly correlated with midazolam clearance in both the CYP3A inhibition and induction phases. We constructed a statistical prediction model after integrating data from a previous study to predict midazolam clearance as follows: Ln(midazolam clearance) = 2.5545 + 0.3988 × ln(7β-OH-DHEA/DHEA) + 0.1984 × ln(16α-OH-DHEA/DHEA) + 0.5031 × ln(6β-OH-cortisol/cortisol) – 0.1261 [ln(7β-OH-DHEA/DHEA) × ln(6β-OH-cortisol/cortisol)] (r2 = 0.75). We suggest that quantitating endogenous markers in vivo coupled with the statistical prediction model may be useful for predicting CYP3A parameters.

Original languageEnglish
Pages (from-to)247-252
Number of pages6
JournalDrug Metabolism and Pharmacokinetics
Volume34
Issue number4
DOIs
StatePublished - 1 Aug 2019

Fingerprint

Cytochrome P-450 CYP3A
Dehydroepiandrosterone
Healthy Volunteers
Midazolam
Liver
Hydrocortisone
Cortisone
Statistical Models
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 CYP3A Inhibitors
Plasma Gases
hydroxide ion
Itraconazole
Androstenedione
Rifampin
Pharmaceutical Preparations
Gas Chromatography-Mass Spectrometry
Urine

Keywords

  • CYP3A
  • Drug-drug interaction
  • Endogenous marker
  • Midazolam
  • Pharmacometabolomics

Cite this

@article{d4377a5145ab406dae56d68387e05aa8,
title = "Quantitative prediction of hepatic CYP3A activity using endogenous markers in healthy subjects after administration of CYP3A inhibitors or inducers",
abstract = "Accurate prediction of cytochrome P450 (CYP) 3A activity in the early stage of drug development and in clinical practice is important. This study aimed to evaluate the previously constructed CYP3A activity prediction model after administration of CYP3A inhibitors and inducers and to modify the model for better prediction of CYP3A activity. Healthy male subjects received the following study drugs during three study periods: midazolam alone (control phase); midazolam with 200 mg of itraconazole (CYP3A inhibition phase); and midazolam with 150 mg of rifampicin (CYP3A induction phase). We quantified the concentrations of several endogenous CYP3A markers in both urine and plasma using gas chromatography-mass spectrometry. The urinary markers, including 6β-hydroxy (OH)-cortisol/cortisol, 6β-OH-cortisone/cortisone, 16α-OH-dehydroepiandrosterone (DHEA)/DHEA, 16α-OH-androstenedione (A-dione)/A-dione and 7β-OH-DHEA/DHEA, were significantly correlated with midazolam clearance in both the CYP3A inhibition and induction phases. We constructed a statistical prediction model after integrating data from a previous study to predict midazolam clearance as follows: Ln(midazolam clearance) = 2.5545 + 0.3988 × ln(7β-OH-DHEA/DHEA) + 0.1984 × ln(16α-OH-DHEA/DHEA) + 0.5031 × ln(6β-OH-cortisol/cortisol) – 0.1261 [ln(7β-OH-DHEA/DHEA) × ln(6β-OH-cortisol/cortisol)] (r2 = 0.75). We suggest that quantitating endogenous markers in vivo coupled with the statistical prediction model may be useful for predicting CYP3A parameters.",
keywords = "CYP3A, Drug-drug interaction, Endogenous marker, Midazolam, Pharmacometabolomics",
author = "J. Lee and Yoon, {Seo Hyun} and Sojeong Yi and Kim, {Andrew Hyoung Jin} and Bora Kim and Lee, {Seung Hwan} and Kyung-Sang Yu and In-Jin Jang and Joo-Youn Cho",
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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, Sojeong; Kim, Andrew Hyoung Jin; Kim, Bora; Lee, Seung Hwan; Yu, Kyung-Sang; Jang, In-Jin; Cho, Joo-Youn.

In: Drug Metabolism and Pharmacokinetics, Vol. 34, No. 4, 01.08.2019, p. 247-252.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Quantitative prediction of hepatic CYP3A activity using endogenous markers in healthy subjects after administration of CYP3A inhibitors or inducers

AU - Lee, J.

AU - Yoon, Seo Hyun

AU - Yi, Sojeong

AU - Kim, Andrew Hyoung Jin

AU - Kim, Bora

AU - Lee, Seung Hwan

AU - Yu, Kyung-Sang

AU - Jang, In-Jin

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AB - Accurate prediction of cytochrome P450 (CYP) 3A activity in the early stage of drug development and in clinical practice is important. This study aimed to evaluate the previously constructed CYP3A activity prediction model after administration of CYP3A inhibitors and inducers and to modify the model for better prediction of CYP3A activity. Healthy male subjects received the following study drugs during three study periods: midazolam alone (control phase); midazolam with 200 mg of itraconazole (CYP3A inhibition phase); and midazolam with 150 mg of rifampicin (CYP3A induction phase). We quantified the concentrations of several endogenous CYP3A markers in both urine and plasma using gas chromatography-mass spectrometry. The urinary markers, including 6β-hydroxy (OH)-cortisol/cortisol, 6β-OH-cortisone/cortisone, 16α-OH-dehydroepiandrosterone (DHEA)/DHEA, 16α-OH-androstenedione (A-dione)/A-dione and 7β-OH-DHEA/DHEA, were significantly correlated with midazolam clearance in both the CYP3A inhibition and induction phases. We constructed a statistical prediction model after integrating data from a previous study to predict midazolam clearance as follows: Ln(midazolam clearance) = 2.5545 + 0.3988 × ln(7β-OH-DHEA/DHEA) + 0.1984 × ln(16α-OH-DHEA/DHEA) + 0.5031 × ln(6β-OH-cortisol/cortisol) – 0.1261 [ln(7β-OH-DHEA/DHEA) × ln(6β-OH-cortisol/cortisol)] (r2 = 0.75). We suggest that quantitating endogenous markers in vivo coupled with the statistical prediction model may be useful for predicting CYP3A parameters.

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