Skip to main content
SpringerLink
Log in

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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Availability of data and materials

Data and materials are available.

Code availability

Not applicable.

References

  1. Aapro M, Gralla RJ, Herrstedt J, Molassiotis A, Roila F (2016) MASCC/ESMO Antiemetic Guidelines. Ver 1:2

    Google Scholar 

  2. Chawla SP, Grunberg SM, Gralla RJ, Hesketh PJ, Rittenberg C, Elmer ME, Schmidt C, Taylor A, Carides AD, Evans JK, Horgan KJ (2003) Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. Cancer 97(9):2290–2300. https://doi.org/10.1002/cncr.11320

    Article  CAS  PubMed  Google Scholar 

  3. Nakade S, Ohno T, Kitagawa J, Hashimoto Y, Katayama M, Awata H, Kodama Y, Miyata Y (2008) Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol 63(1):75–83. https://doi.org/10.1007/s00280-008-0713-y

    Article  CAS  PubMed  Google Scholar 

  4. Hibino H, Makino Y, Sakiyama N, Makihara-Ando R, Hashimoto H, Akiyoshi T, Imaoka A, Fujiwara Y, Ohe Y, Yamaguchi M, Ohtani H (2021) Exacerbation of atrioventricular block associated with concomitant use of amlodipine and aprepitant in a lung cancer patient. Int J Clin Pharmacol Ther 59(4):328. https://doi.org/10.5414/CP203758

    Article  PubMed  Google Scholar 

  5. Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, Evans JK, Blum RA (2004) Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 44(3):215–223. https://doi.org/10.1177/0091270003262950

    Article  CAS  PubMed  Google Scholar 

  6. Villikka K, Kivistö KT, Neuvonen PJ (1998) The effect of dexamethasone on the pharmacokinetics of triazolam. Pharmacol Toxicol 83(3):135–138. https://doi.org/10.1111/j.1600-0773.1998.tb01457.x

    Article  CAS  PubMed  Google Scholar 

  7. Hoek J, Bloemendal KM, van der Velden LA et al (2016) Nephrotoxicity as a dose-limiting factor in a high-dose cisplatin-based chemoradiotherapy regimen for head and neck carcinomas. Cancers (Basel) 8(2):21. https://doi.org/10.3390/cancers8020021

    Article  CAS  Google Scholar 

  8. Hoek J, Bloemendal KM, van der Velden LA, van Diessen JN, van Werkhoven E, Klop WM, Tesselaar ME (2009) Assessment of the impact of renal impairment on systemic exposure of new molecular entities: evaluation of recent new drug applications. Clin Pharmacol Ther 85(3):305–311. https://doi.org/10.1038/clpt.2008.208

    Article  CAS  Google Scholar 

  9. Yeung CK, Shen DD, Thummel KE, Himmelfarb J (2014) Effects of chronic kidney disease and uremia onhepatic drug metabolism and transport. Kidney Int 85(3):522–528. https://doi.org/10.1038/ki.2013.399

    Article  CAS  PubMed  Google Scholar 

  10. Yamamoto N, Tamura T, Kamiya Y, Sekine I, Kunitoh H, Saijo N (2000) Correlation between docetaxel clearance and estimated cytochrome P450 activity by urinary metabolite of exogenous cortisol. J Clin Oncol 18(11):2301–2308. https://doi.org/10.1200/JCO.2000.18.11.2301

    Article  CAS  PubMed  Google Scholar 

  11. Yamamoto N, Tamura T, Murakami H, Shimoyama T, Nokihara H, Ueda Y, Sekine I, Kunitoh H, Ohe Y, Kodama T, Shimizu M, Nishio K, Ishizuka N, Saijo N (2005) Randomized pharmacokinetic and pharmacodynamic study of docetaxel: dosing based on body-surface area compared with individualized dosing based on cytochrome P450 activity estimated using a urinary metabolite of exogenous cortisol. J Clin Oncol 23(3):1061–1069. https://doi.org/10.1200/JCO.2005.11.036

    Article  CAS  PubMed  Google Scholar 

  12. Shin KH, Choi MH, Lim KS, Yu KS, Jang IJ, Cho JY (2013) Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance. Clin Pharmacol Ther 94(5):601–609. https://doi.org/10.1038/clpt.2013.128

    Article  CAS  PubMed  Google Scholar 

  13. Moon JY, Kang SM, Lee J, Cho JY, Moon MH, Jang IJ, Chung BC, Choi MH (2013) GC-MS–Based quantitative signatures of cytochrome P450–mediated steroid oxidation induced by rifampicin. Ther Drug Monit 35(4):473–484. https://doi.org/10.1097/FTD.0b013e318286ee02

    Article  CAS  PubMed  Google Scholar 

  14. Bodin K, Bretillon L, Aden Y, Bertilsson L, Broomé U, Einarsson C, Diczfalusy U (2001) Antiepileptic drugs increase plasma levels of 4β-hydroxycholesterol in humans. J Biol Chem 276(42):38685–38689. https://doi.org/10.1074/jbc.M105127200

    Article  CAS  PubMed  Google Scholar 

  15. Kanebratt KP, Diczfalusy U, Bäckström T, Sparve E, Bredberg E, Böttiger Y, Andersson TB, Bertilsson L (2008) Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4β-hydroxycholesterol. Clin Pharmacol Ther 84(5):589–594. https://doi.org/10.1038/clpt.2008.132

    Article  CAS  PubMed  Google Scholar 

  16. Nakagawa S, Yamamoto S (2011) High sensitive determination of oxysterols in human plasma using gas chromatography-mass spectrometry (GC-MS). The Society of Analytical Bio-Science 35(2):119–126. (in Japanese)

  17. Lac G, Marquet P, Chassain AP, Galen FX (1999) Dexamethasone in resting and exercising men. II. Effects on adrenocortical hormones. J Appl Physiol 87(1):183–188. https://doi.org/10.1152/jappl.1999.87.1.183

  18. Henriksen JE, Alford F, Ward GM, Beck-Nielsen H (1997) Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients. Diabetologia 40(12):1439–1448. https://doi.org/10.1007/s001250050847

    Article  CAS  PubMed  Google Scholar 

  19. Saiz-Rodríguez M, Almenara S, Navares-Gómez M, Ochoa D, Román M, Zubiaur P, Koller D, Santos M, Mejía G, Borobia AM, Rodríguez-Antona C, Abad-Santos F (2020) Effect of the most relevant CYP3A4 and CYP3A5 polymorphisms on the pharmacokinetic parameters of 10 CYP3A substrates. Biomedicines 8(4):94. https://doi.org/10.3390/biomedicines8040094

    Article  CAS  PubMed Central  Google Scholar 

  20. Moon JY, Moon MH, Kim KT, Jeong DH, Kim YN, Chung BC, Choi MH (2014) Cytochrome P450-mediated metabolic alterations in preeclampsia evaluated by quantitative steroid signatures. J Steroid Biochem Mol Biol 139:182–191. https://doi.org/10.1016/j.jsbmb.2013.02.014

    Article  CAS  PubMed  Google Scholar 

  21. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27(4):383–391. https://doi.org/10.1038/86882

    Article  CAS  PubMed  Google Scholar 

  22. Motohashi S, Mino Y, Hori K, Naito T, Hosokawa S, Furuse H, Ozono S, Mineta H, Kawakami J (2013) Interindividual variations in aprepitant plasma pharmacokinetics in cancer patients receiving cisplatin-based chemotherapy for the first time. Biol Pharm Bull 36(4):676–681. https://doi.org/10.1248/bpb.b12-01086

    Article  CAS  PubMed  Google Scholar 

  23. van Schaik RH, van der Heiden IP, van den Anker JN, Lindemans J (2002) CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 48(10):1668–1671

    Article  Google Scholar 

  24. Stoch SA, Gargano C, Valentine J, Braun MP, Murphy MG, Fedgchin M, Majumdar A, Pequignot E, Gottesdiener KM, Petty KJ, Panebianco D, Dean D, Kraft WK, Greenberg HE (2011) Double-blind crossover study to assess potential differences in cytochrome P450 3A4 activity in healthy subjects receiving ondansetron plus dexamethasone, with and without aprepitant. Cancer Chemother Pharmacol 67(6):1313–1321. https://doi.org/10.1007/s00280-010-1421-y

    Article  CAS  PubMed  Google Scholar 

  25. Levêque D, Jehl F (1996) Clinical pharmacokinetics of vinorelbine. Clin Pharmacokinet 31(3):184–197. https://doi.org/10.2165/00003088-199631030-00003

    Article  PubMed  Google Scholar 

  26. Mangold JB, Wu F, Rebello S (2016) Compelling relationship of CYP3A induction to levels of the putative biomarker 4β-hydroxycholesterol and changes in midazolam exposure. Clin Pharmacol Drug Dev 5(4):245–249. https://doi.org/10.1002/cpdd.265

    Article  CAS  PubMed  Google Scholar 

  27. ONO Pharmaceutical Co., Ltd (2020) Interview form of EMEND® capsules (11th edn). (in Japanese). https://www.ono-oncology.jp/system/files/2020-11/EM_IF_0.pdf. Accessed 17 Jan 2022

  28. Endo T, Saijo T, Haneda E, Maeda J, Tokunaga M, Zhang MR, Kannami A, Asai H, Suzuki M, Suhara T, Higuchi M (2014) Quantification of central substance P receptor occupancy by aprepitant using small animal positron emission tomography. Int J Neuropsychopharmacol 18(2):1–10. https://doi.org/10.1093/ijnp/pyu030

    Article  CAS  Google Scholar 

  29. Sanchez RI, Wang RW, Newton DJ, Bakhtiar R, Lu P, Chiu SH, Evans DC, Huskey SE (2004) Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the substance P receptor antagonist aprepitant. Drug Metab Dispos 32:1287–1292. https://doi.org/10.1124/dmd.104.000216

    Article  CAS  PubMed  Google Scholar 

  30. Diczfalusy U, Nylén H, Elander P, Bertilsson L (2011) 4β-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol 71(2):183–189. https://doi.org/10.1111/j.1365-2125.2010.03773.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ishida T, Naito T, Sato H, Kawakami J (2016) Relationship between the plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain. Drug Metab Pharmacokinet 31(3):242–248. https://doi.org/10.1016/j.dmpk.2016.04.001

    Article  CAS  PubMed  Google Scholar 

  32. Rodríguez-Morató J, Goday A, Langohr K, Pujadas M, Civit E, Pérez-Mañá C, Papaseit E, Ramon JM, Benaiges D, Castañer O, Farré M, de la Torre R (2019) Short- and medium-term impact of bariatric surgery on the activities of CYP2D6, CYP3A4, CYP2C9, and CYP1A2 in morbid obesity. Sci Rep 9(1):20405. https://doi.org/10.1038/s41598-019-57002-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Arlt W, Justl HG, Callies F, Reincke M, Hübler D, Oettel M, Ernst M, Schulte HM, Allolio B (1998) Oral Dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 83(6):1928–1934. https://doi.org/10.1210/jcem.83.6.4850

    Article  CAS  PubMed  Google Scholar 

  34. Choi MH, Skipper PL, Wishnok JS, Tannenbaum SR (2005) Characterization of testosterone 11β-hydroxylation catalyzed by human liver microsomal cytochromes P450. Drug Metab Dispos 33(6):714–718. https://doi.org/10.1124/dmd.104.003327

    Article  CAS  PubMed  Google Scholar 

  35. Bodin K, Andersson U, Rystedt E, Ellis E, Norlin M, Pikuleva I, Eggertsen G, Björkhem I, Diczfalusy U (2002) Metabolism of 4β-hydroxycholesterol in humans. J Biol Chem 277(35):31534–31540. https://doi.org/10.1074/jbc.M201712200

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacokinetics, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan

    Hideyuki Hibino, Takeshi Akiyoshi, Ayuko Imaoka & Hisakazu Ohtani

  2. Department of Pharmacy, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hideyuki Hibino, Naomi Sakiyama, Reiko Makihara-Ando, Hironobu Hashimoto & Masakazu Yamaguchi

  3. Department of Cancer Genome Medicine, Department of Pharmacy, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1298, Japan

    Yoshinori Makino

  4. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hidehito Horinouchi, Yutaka Fujiwara, Shintaro Kanda, Yasushi Goto, Tatsuya Yoshida, Yusuke Okuma, Yuki Shinno, Shuji Murakami & Yuichiro Ohe

  5. Keio University School of Medicine, Tokyo, Japan, 35, Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan

    Hisakazu Ohtani

  6. Keio University Hospital, Department of Pharmacy, Tokyo, Japan, 35, Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan

    Hisakazu Ohtani

Authors
  1. Hideyuki Hibino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naomi Sakiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshinori Makino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reiko Makihara-Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hidehito Horinouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yutaka Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shintaro Kanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasushi Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tatsuya Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yusuke Okuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuki Shinno
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shuji Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hironobu Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Takeshi Akiyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ayuko Imaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yuichiro Ohe
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Masakazu Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hisakazu Ohtani
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Hideyuki Hibino designed the study, performed the research, conducted the experiments on humans, analyzed the data, and wrote the manuscript. Naomi Sakiyama recruited the participants and reviewed the manuscript. Yoshinori Makino designed the study, performed the research, reviewed the manuscript, and participated in the conception of the study. Reiko Makihara-Ando performed the research, reviewed the manuscript, and participated in the conception of the study. Hidehito Horinouchi, Yutaka Fujiwara, Shintaro Kanda, Yasushi Goto, Tatsuya Yoshida, Yusuke Okuma, Yuki Shinno, and Shuji Murakami recruited the participants, reviewed the manuscript, and monitored the participants medically. Hironobu Hashimoto, Takeshi Akiyoshi, and Ayuko Imaoka reviewed the manuscript and participated in the conception of the study. Yuichiro Ohe designed the study, reviewed the manuscript, and participated in the conception of the study. Masakazu Yamaguchi reviewed the manuscript and participated in the conception of the study. Hisakazu Ohtani designed the study and reviewed the manuscript at conception and at the final stage.

Corresponding author

Correspondence to Hisakazu Ohtani.

Ethics declarations

Ethics approval

Ethical approval was obtained from the Ethics Committee of the National Cancer Center Hospital and Keio University.

Consent to participate

All authors gave their consent to participate in the study.

Consent for publication

All authors gave consent to publish the article in the European Journal of Clinical Pharmacology.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

228_2022_3275_MOESM1_ESM.pdf

Supplementary file1 fig. 1 Treatment schedule for chemotherapy and antiemetic therapy. CDDP: 80 mg/m2 (Day 1) + VNR: (20 ~) 25 mg/m2 (Days 1, 8) ± TRT. CDDP : 80 mg/m2 (Day1) + PEM: 500 mg/m2 (Day 1). APR : 125 mg (Day 1), 80 mg (Days 2, 3). PALO : 0.75 mg (Day 1). DEX : 9.9 mg (Day 1), 8 mg (Days 2-5). CDDP: cisplatin, VNR; vinorelbine, TRT; Thoracic Radiotherapy, PEM; pemetrexed, APR; aprepitant, PALO; palonosetron, DEX; dexamethasone (PDF 363 KB)

Supplementary file2 fig. 2 Correlation between the plasma concentration of 4β-OHC and BMI on day 1 (PDF 502 KB)

Supplementary file3 (PDF 205 KB)

Supplementary file4 (PDF 108 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hibino, H., Sakiyama, N., Makino, Y. et al. Evaluation of hepatic CYP3A enzyme activity using endogenous markers in lung cancer patients treated with cisplatin, dexamethasone, and aprepitant. Eur J Clin Pharmacol 78, 613–621 (2022). https://doi.org/10.1007/s00228-022-03275-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-022-03275-5

Keywords

Search

Navigation