Metabolite profiling and enzyme reaction phenotyping of luseogliflozin, a sodium–glucose cotransporter 2 inhibitor, in humans

Xenobiotica

Volumn 47, Issue 4, 2017, Pages 332-345

  Miyata, Atsunori ^a   Hasegawa, Masatoshi ^a   Hachiuma, Kenji ^a   Mori, Haruyuki ^a   Horiuchi, Nobuko ^a   Mizuno Yasuhira, Akiko ^a   Chino, Yukihiro ^a   Jingu, Shigeji ^a   Sakai, Soichi ^a   Samukawa, Yoshishige ^a   Nakai, Yasuhiro ^a   Yamaguchi, Jun Ichi ^a  

^a TAISHO PHARMACEUTICAL CO LTD   (Japan)

Author keywords

CYP; luseogliflozin; metabolism; SGLT2 inhibitor; UGT

Indexed keywords

ALCOHOL DEHYDROGENASE; ALDEHYDE DEHYDROGENASE; CARBOXYLIC ACID; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; CYTOCHROME P450 4A11; CYTOCHROME P450 4F2; CYTOCHROME P450 4F3B; DRUG METABOLITE; GLUCURONOSYLTRANSFERASE 1A1; GLUCURONOSYLTRANSFERASE 1A8; GLUCURONOSYLTRANSFERASE 1A9; LUSEOGLIFLOZIN; PLACEBO; UNCLASSIFIED DRUG; 1,5-ANHYDRO-1-(5-(4-ETHOXYBENZYL)-2-METHOXY-4-METHYLPHENYL)-1-THIOGLUCITOL; CYP3A4 PROTEIN, HUMAN; CYTOCHROME P450; CYTOCHROME P450 3A; GLUCOSE; GLUCURONOSYLTRANSFERASE; SODIUM GLUCOSE COTRANSPORTER 2; SORBITOL; UDP-GLUCURONOSYLTRANSFERASE 1A9; UDP-GLUCURONOSYLTRANSFERASE, UGT1A8; UGT1A1 ENZYME;

ARTICLE; BLOOD SAMPLING; CONTROLLED STUDY; DRUG CLEARANCE; DRUG DETERMINATION; DRUG GLUCURONIDATION; DRUG HYDROXYLATION; DRUG METABOLISM; DRUG OXIDATION; DRUG PROTEIN BINDING; DRUG STRUCTURE; ENZYME MECHANISM; HUMAN; IN VIVO STUDY; LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY; LIVER MICROSOME; NON INSULIN DEPENDENT DIABETES MELLITUS; PHASE 1 CLINICAL TRIAL; PHENOTYPE; PLASMA CONCENTRATION-TIME CURVE; RANDOMIZED CONTROLLED TRIAL; SINGLE BLIND PROCEDURE; URINE SAMPLING; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; HYDROXYLATION; KINETICS; METABOLISM; OXIDATION REDUCTION REACTION;

CYTOCHROME P-450 CYP3A; CYTOCHROME P-450 ENZYME SYSTEM; GLUCOSE; GLUCURONOSYLTRANSFERASE; HUMANS; HYDROXYLATION; KINETICS; METABOLIC NETWORKS AND PATHWAYS; MICROSOMES, LIVER; OXIDATION-REDUCTION; SODIUM-GLUCOSE TRANSPORTER 2; SORBITOL;

EID: 84976273800     PISSN: 00498254     EISSN: 13665928     Source Type: Journal    
DOI: 10.1080/00498254.2016.1193263     Document Type: Article

References (55)

1. Bailey CJ., (2011). Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci 32:63–71.
2. Bjornsson TD, Callaghan JT, Einolf HJ, et al. (2003). The conduct of in vitro and in vivo drug-drug interaction studies:a PhRMA perspective. J Clin Pharmacol 43:443–69.
3. Chen LZ, Jungnik A, Mao Y, et al. (2014). Biotransformation and mass balance of the SGLT2 inhibitor empagliflozin in healthy volunteers. Xenobiotica 45:520–9.
4. Dostalek M, Court MH, Hazarika S, Akhlaghi F., (2011). Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite. Drug Metab Dispos 39:448–55.
5. Edwards RJ, Adams DA, Watts PS, et al. (1998). Development of a comprehensive panel of antibodies against the major xenobiotic metabolising forms of cytochrome P450 in humans. Biochem Pharmacol 56:377–87.
6. Elkinson S, Scott LJ., (2013). Canagliflozin:first global approval. Drugs 73:979–88.
7. Engel G, Hofmann U, Heidemann H, et al. (1996). Antipyrine as a probe for human oxidative drug metabolism:identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. Clin Pharmacol Ther 59:613–23.
8. Ferrannini E, Veltkamp SA, Smulders RA, Kadokura T., (2013). Renal glucose handling:impact of chronic kidney disease and sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care 36:1260–5.
9. Fisher MB, Paine MF, Strelevitz TJ, Wrighton SA., (2001). The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metab Rev 33:273–97.
10. Freeman JS., (2013). Review of insulin-dependent and insulin-independent agents for treating patients with type 2 diabetes mellitus and potential role for sodium-glucose co-transporter 2 inhibitors. Postgrad Med 125:214–26.
11. Furlan V, Demirdjian S, Bourdon O, et al. (1999). Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther 289:1169–75.
12. Haneda M, Yutaka S, Sasaki S, et al. (2012). The Effect of Luseogliflozin (TS-071), a Selective SGLT2 inhibitor, on Pharmacodynamics and Pharmacokinetics in Japanese Type 2 Diabetic Subjects with Renal Impairment. American Diabetes Association 72nd Scientific Session, Philadelphia, PA, USA, Jun 8-12, 2012. Poster Session 1062-P.
13. Hasegawa M, Chino Y, Horiuchi N, et al. (2015). Preclinical metabolism and disposition of luseogliflozin, a novel antihyperglycemic agent. Xenobiotica 45:1105–15.
14. Hashizume T, Imaoka S, Hiroi T, et al. (2001). cDNA cloning and expression of a novel cytochrome p450 (cyp4f12) from human small intestine. Biochem Biophys Res Commun 280:1135–41.
15. Hashizume T, Imaoka S, Mise M, et al. (2002). Involvement of CYP2J2 and CYP4F12 in the metabolism of ebastine in human intestinal microsomes. J Pharmacol Exp Ther 300:298–304.
16. Hsu MH, Savas U, Griffin KJ, Johnson EF., (2007). Human cytochrome p450 family 4 enzymes:function, genetic variation and regulation. Drug Metab Rev 39:515–38.
17. Iwamoto M, Hanley WD, Petry AS, et al. (2009). Lack of a clinically important effect of moderate hepatic insufficiency and severe renal insufficiency on raltegravir pharmacokinetics. Antimicrob Agents Chemother 53:1747–52.
18. Jin Y, Zollinger M, Borell H, et al. (2011). CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis. Drug Metab Dispos 39:191–8.
19. Kamdem LK, Flockhart DA, Desta Z., (2011). In vitro cytochrome P450-mediated metabolism of exemestane. Drug Metab. Dispos 39:98–105.
20. Kassam JP, Tang BK, Kadar D, Kalow W., (1989). In vitro studies of human liver alcohol dehydrogenase variants using a variety of substrates. Drug Metab Dispos 17:567–72.
21. Kim JH, Sherman ME, Curriero FC, et al. (2004). Expression of cytochromes P450 1A1 and 1B1 in human lung from smokers, non-smokers, and ex-smokers. Toxicol Appl Pharmacol 199:210–19.
22. Komen JC, Wanders RJ., (2006). Identification of the cytochrome P450 enzymes responsible for the omega-hydroxylation of phytanic acid. FEBS Lett 580:3794–8.
23. Lam JP, Mays DC, Lipsky JJ., (1997). Inhibition of recombinant human mitochondrial and cytosolic aldehyde dehydrogenases by two candidates for the active metabolites of disulfiram. Biochemistry 36:13748–54.
24. Leslie EM, Deeley RG, Cole SP., (2005). Multidrug resistance proteins:role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204:216–37.
25. Linder CD, Renaud NA, Hutzler JM., (2009). Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metab Dispos 37:10–13.
26. Marill J, Cresteil T, Lanotte M, Chabot GG., (2000). Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol Pharmacol 58:1341–8.
27. Matzke GR, Frye RF, Early JJ, et al. (2000). Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity. Pharmacotherapy 20:182–90.
28. Mizuno-Yasuhira A, Nakai Y, Gunji E, et al. (2014). A Strategy for assessing potential drug-drug interactions of a concomitant agent against a drug absorbed via an intestinal transporter in humans. Drug Metab Dispos 42:1456–65.
29. Nakamura A, Nakajima M, Yamanaka H, et al. (2008). Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines. Drug Metab Dispos 36:1461–4.
30. Ohno S, Nakajin S., (2009). Determination of mRNA expression of human UDP-Glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab Dispos 37:32–40.
31. Package Insert of Lusefi. (2015). Available from:https://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/400059_3969020F1020_1_06 [Japanese] [last accessed 8 Feb 2016].
32. Paine MF, Hart HL, Ludington SS, et al. (2006). The human intestinal cytochrome P450 “pie”. Drug Metab Dispos 34:880–6.
33. Pavek P, Dvorak Z., (2008). Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues. Curr Drug Metab 9:129–43.
34. Plosker GL., (2012). Dapagliflozin:a review of its use in type 2 diabetes mellitus. Drugs 72:2289–312.
35. Poole RM, Dungo RT., (2014a). Ipragliflozin:first global approval. Drugs 74:611–17.
36. Poole RM, Prossler JE., (2014b). Tofogliflozin:first global approval. Drugs 74:939–44.
37. Santer R, Kinner M, Lassen CL, et al. (2003). Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 14:2873–82.
38. Sasaki T, Seino Y, Fukatsu A, et al. (2014). Safety, pharmacokinetics, and pharmacodynamics of single and multiple luseogliflozin dosing in healthy Japanese males:a randomized, single-blind, placebo-controlled trial. Adv Ther 31:345–61.
39. Sasaki T, Seino Y, Fukatsu A, et al. (2015). Pharmacokinetics, pharmacodynamics, and safety of luseogliflozin in Japanese patients with type 2 diabetes mellitus:a randomized, single-blind, placebo-controlled trial. Adv Ther 32:319–40.
40. Schweikl H, Taylor JA, Kitareewan S, et al. (1993). Expression of CYP1A1 and CYP1A2 genes in human liver. Pharmacogenetics 3:239–49.
41. Scott LJ., (2014). Empagliflozin:a review of its use in patients with type 2 diabetes mellitus. Drugs 74:1769–84.
42. Seino Y, Sasaki T, Fukatsu A, et al. (2014). Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus:a randomized, double-blind, placebo-controlled, phase 3 study. Curr Med Res Opin 30:1245–55.
43. Seino Y., (2014). Luseogliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother 15:2741–9.
44. Song IH, Borland J, Savina PM, et al. (2013). Pharmacokinetics of single-dose dolutegravir in HIV-seronegative subjects with moderate hepatic impairment compared to healthy matched controls. Clin Pharmacol Drug Dev 2:342–8.
45. Uchida S, Mitani A, Gunji E, et al. (2015). In vitro characterization of luseogliflozin, a potent and competitive sodium glucose co-transporter 2 inhibitor:inhibition kinetics and binding studies. J Pharmacol Sci 128:54–7.
46. Verbeeck RK., (2008). Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 64:1147–61.
47. Wang MZ, Saulter JY, Usuki E, et al. (2006). CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime]. Drug Metab Dispos 34:1985–94.
48. Wang MZ, Wu JQ, Bridges AS, et al. (2007). Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine. Drug Metab Dispos 35:2067–75.
49. Wang Z, Hall SD, Maya JF, et al. (2003). Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. Br J Clin Pharmacol 55:77–85.
50. Wright EM., (2001). Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol 280:F10–18.
51. Yamamoto K, Uchida S, Kitano K, et al. (2011). TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity. Br J Pharmacol 164:181–91.
52. Yamane M, Kawashima K, Yamaguchi K, et al. (2015). In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP. Xenobiotica 45:230–8.
53. Zhang H, Davis CD, Sinz MW, Rodrigues AD., (2007). Cytochrome P450 reaction-phenotyping:an industrial perspective. Expert Opin Drug Metab Toxicol 3:667–87.
54. Zhang JY, Wang Y, Prakash C., (2006). Xenobiotic-metabolizing enzymes in human lung. Curr Drug Metab 7:939–48.
55. Zhang L, Zhang YD, Zhao P, Huang SM., (2009). Predicting drug-drug interactions:an FDA perspective. AAPS J 11:300–6.