Hideyuki Hibino1,2, Naomi Sakiyama2, Yoshinori Makino3, Reiko Makihara-Ando2, Hidehito Horinouchi4, Yutaka Fujiwara4, Shintaro Kanda4, Yasushi Goto4, Tatsuya Yoshida4, Yusuke Okuma4, Yuki Shinno4, Shuji Murakami4, Hironobu Hashimoto2, Takeshi Akiyoshi1, Ayuko Imaoka1, Yuichiro Ohe4, Masakazu Yamaguchi2, Hisakazu Ohtani5,6,7. 1. Division of Clinical Pharmacokinetics, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. 2. Department of Pharmacy, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. 3. Department of Cancer Genome Medicine, Department of Pharmacy, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1298, Japan. 4. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. 5. Division of Clinical Pharmacokinetics, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. ohtani-tky@umin.net. 6. Keio University School of Medicine, Tokyo, Japan, 35, Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan. ohtani-tky@umin.net. 7. Keio University Hospital, Department of Pharmacy, Tokyo, Japan, 35, Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan. ohtani-tky@umin.net.
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.
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.
Authors: Sant P Chawla; Steven M Grunberg; Richard J Gralla; Paul J Hesketh; Cindy Rittenberg; Mary E Elmer; Carrie Schmidt; Arlene Taylor; Alexandra D Carides; Judith K Evans; Kevin J Horgan Journal: Cancer Date: 2003-05-01 Impact factor: 6.860
Authors: Craig R Shadle; Yih Lee; Anup K Majumdar; Kevin J Petty; Cynthia Gargano; Thomas E Bradstreet; Judith K Evans; Robert A Blum Journal: J Clin Pharmacol Date: 2004-03 Impact factor: 3.126