Metabolites of Alectinib in Human: Their Identification and Pharmacological Activity

Overview

Journal Heliyon

Specialty Social Sciences

Date 2017 Jul 21

PMID 28725874

Citations 6

Authors

Mika Sato-Nakai

Kosuke Kawashima

Toshito Nakagawa

Yukako Tachibana

Miyuki Yoshida

Kenji Takanashi

Peter N Morcos

Martin Binder

David J Moore

Li Yu

Affiliations

Soon will be listed here.

Abstract

Two metabolites (M4 and M1b) in plasma and four metabolites (M4, M6, M1a and M1b) in faeces were detected through the human ADME study following a single oral administration of [C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to pharmacological activity of these circulating metabolites was assessed from their pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant.

Citing Articles

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Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib.

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References

Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami T . CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011; 19(5):679-90. DOI: 10.1016/j.ccr.2011.04.004. View

Slatter J, Stalker D, Feenstra K, Welshman I, Bruss J, Sams J . Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [(14)C]linezolid to healthy human subjects. Drug Metab Dispos. 2001; 29(8):1136-45. View

Ballard T, Wang S, Cox L, Moen M, Krzyzewski S, Ukairo O . Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism. Drug Metab Dispos. 2015; 44(2):172-9. DOI: 10.1124/dmd.115.066688. View

Wang Z, Cirino P . New and improved tools and methods for enhanced biosynthesis of natural products in microorganisms. Curr Opin Biotechnol. 2016; 42:159-168. DOI: 10.1016/j.copbio.2016.05.003. View

Nguyen H, Callegari E, Obach R . The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine. Drug Metab Dispos. 2016; 44(10):1569-78. DOI: 10.1124/dmd.116.071639. View

Avrillon V, Perol M . Alectinib for treatment of ALK-positive non-small-cell lung cancer. Future Oncol. 2016; 13(4):321-335. DOI: 10.2217/fon-2016-0386. View

Leclercq L, Cuyckens F, Mannens G, de Vries R, Timmerman P, Evans D . Which human metabolites have we MIST? Retrospective analysis, practical aspects, and perspectives for metabolite identification and quantification in pharmaceutical development. Chem Res Toxicol. 2009; 22(2):280-93. DOI: 10.1021/tx800432c. View

Denissen J, Grabowski B, Johnson M, Boyd S, Uchic J, STEIN H . The orally active renin inhibitor A-74273. In vivo and in vitro morpholine ring metabolism in rats, dogs, and humans. Drug Metab Dispos. 1994; 22(6):880-8. View

Wang W, Khetani S, Krzyzewski S, Duignan D, Obach R . Assessment of a micropatterned hepatocyte coculture system to generate major human excretory and circulating drug metabolites. Drug Metab Dispos. 2010; 38(10):1900-5. DOI: 10.1124/dmd.110.034876. View

10.

Johnson T, Tan W, Goulet L, Smith E, Yamazaki S, Walker G . Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects. Xenobiotica. 2014; 45(1):45-59. DOI: 10.3109/00498254.2014.941964. View

11.

Gao R, Li L, Xie C, Diao X, Zhong D, Chen X . Metabolism and pharmacokinetics of morinidazole in humans: identification of diastereoisomeric morpholine N+-glucuronides catalyzed by UDP glucuronosyltransferase 1A9. Drug Metab Dispos. 2011; 40(3):556-67. DOI: 10.1124/dmd.111.042689. View

12.

Ballard T, Orozco C, Obach R . Generation of major human excretory and circulating drug metabolites using a hepatocyte relay method. Drug Metab Dispos. 2014; 42(5):899-902. DOI: 10.1124/dmd.114.057026. View

13.

Schiller J, Harrington D, Belani C, Langer C, Sandler A, Krook J . Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002; 346(2):92-8. DOI: 10.1056/NEJMoa011954. View

14.

Morcos P, Yu L, Bogman K, Sato M, Katsuki H, Kawashima K . Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects. Xenobiotica. 2016; 47(3):217-229. DOI: 10.1080/00498254.2016.1179821. View

15.

Morcos P, Cleary Y, Guerini E, Dall G, Bogman K, De Petris L . Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib. Clin Pharmacol Drug Dev. 2016; 6(3):280-291. DOI: 10.1002/cpdd.298. View

16.

Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D . Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos. 2009; 37(5):1056-64. DOI: 10.1124/dmd.108.025569. View

17.

Kwak E, Bang Y, Camidge D, Shaw A, Solomon B, Maki R . Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010; 363(18):1693-703. PMC: 3014291. DOI: 10.1056/NEJMoa1006448. View

18.

Roffey S, Obach R, Gedge J, Smith D . What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev. 2007; 39(1):17-43. DOI: 10.1080/03602530600952172. View

19.

Shinmura K, Kageyama S, Tao H, Bunai T, Suzuki M, Kamo T . EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. Lung Cancer. 2008; 61(2):163-9. DOI: 10.1016/j.lungcan.2007.12.013. View

20.

McKillop D, Hutchison M, Partridge E, Bushby N, Cooper C, Clarkson-Jones J . Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man. Xenobiotica. 2005; 34(10):917-34. DOI: 10.1080/00498250400009171. View