Evaluation of hepatic CYP3A enzyme activity using endogenous markers in lung cancer patients treated with cisplatin, dexamethasone, and aprepitant

Hideyuki Hibino, Naomi Sakiyama, Yoshinori Makino, Reiko Makihara-Ando, Hidehito Horinouchi, Yutaka Fujiwara, Shintaro Kanda, Yasushi Goto, Tatsuya Yoshida, Yusuke Okuma, Yuki Shinno, Shuji Murakami, Hironobu Hashimoto, Takeshi Akiyoshi, Ayuko Imaoka, Yuichiro Ohe, Masakazu Yamaguchi, Hisakazu Ohtani

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Aprepitant is used with dexamethasone and 5-HT3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant. Methods: Urinary 11β-hydroxytestosterone (11β-OHT)/testosterone concentration ratio and plasma 4β-hydroxycholesterol (4β-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers. Results: The urinary 11β-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4β-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4β-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy. Conclusion: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.

Original languageEnglish
Pages (from-to)613-621
Number of pages9
JournalEuropean Journal of Clinical Pharmacology
Volume78
Issue number4
DOIs
Publication statusPublished - 2022 Apr

Keywords

  • 11β-hydroxytestosterone/testosterone
  • 4β-hydroxycholesterol
  • Aprepitant
  • CYP3A endogenous marker
  • CYP3A4/5 induction
  • NSCLC

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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