Species differences in the CYP3A-catalyzed metabolism of TPN729, a novel PDE5 inhibitor.
CYP3A4
M3
PDE5 inhibitor
TPN729
metabolite identification
pharmacokinetics
species difference
Journal
Acta pharmacologica Sinica
ISSN: 1745-7254
Titre abrégé: Acta Pharmacol Sin
Pays: United States
ID NLM: 100956087
Informations de publication
Date de publication:
Mar 2021
Mar 2021
Historique:
received:
30
11
2019
accepted:
17
05
2020
pubmed:
26
6
2020
medline:
10
9
2021
entrez:
26
6
2020
Statut:
ppublish
Résumé
TPN729 is a novel phosphodiesterase 5 (PDE5) inhibitor used to treat erectile dysfunction in men. Our previous study shows that the plasma exposure of metabolite M3 (N-dealkylation of TPN729) in humans is much higher than that of TPN729. In this study, we compared its metabolism and pharmacokinetics in different species and explored the contribution of its main metabolite M3 to pharmacological effect. We conducted a combinatory approach of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolite identification, and examined pharmacokinetic profiles in monkeys, dogs, and rats following TPN729 administration. A remarkable species difference was observed in the relative abundance of major metabolite M3: i.e., the plasma exposure of M3 was 7.6-fold higher than that of TPN729 in humans, and 3.5-, 1.2-, 1.1-fold in monkeys, dogs, and rats, respectively. We incubated liver S9 and liver microsomes with TPN729 and CYP3A inhibitors, and demonstrated that CYP3A was responsible for TPN729 metabolism and M3 formation in humans. The inhibitory activity of M3 on PDE5 was 0.78-fold that of TPN729 (The IC
Identifiants
pubmed: 32581257
doi: 10.1038/s41401-020-0447-x
pii: 10.1038/s41401-020-0447-x
pmc: PMC8027186
doi:
Substances chimiques
Phosphodiesterase 5 Inhibitors
0
Pyrimidinones
0
Sulfonamides
0
TPN729
0
Cytochrome P-450 CYP3A
EC 1.14.14.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
482-490Références
Allen MS, Walter EE. Erectile dysfunction: an umbrella review of meta-analyses of risk-factors, treatment, and prevalence outcomes. J Sex Med. 2019;16:531–41.
doi: 10.1016/j.jsxm.2019.01.314
Lotti F, Maggi M. Sexual dysfunction and male infertility. Nat Rev Urol. 2018;15:287–307.
doi: 10.1038/nrurol.2018.20
Andersson KE. PDE5 inhibitors—pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol. 2018;175:2554–65.
doi: 10.1111/bph.14205
Wang Z, Zhu DF, Yang XC, Li JF, Jiang XR, Tian GH, et al. The selectivity and potency of the new PDE5 inhibitor TPN729MA. J Sex Med. 2013;10:2790–7.
doi: 10.1111/jsm.12285
Warrington JS, Shader RI, von Moltke LL, Greenblatt DJ. In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions. Drug Metab Dispos. 2000;28:392–7.
pubmed: 10725306
Warrington JS, von Moltke LL, Harmatz JS, Shader RI, Greenblatt DJ. The effect of age on sildenafil biotransformation in rat and mouse liver microsomes. Drug Metab Dispos. 2003;31:1306–9.
doi: 10.1124/dmd.31.11.1306
Lee SK, Kim DH, Yoo HH. Comparative metabolism of sildenafil in liver microsomes of different species by using LC/MS-based multivariate analysis. J Chromatogr B Anal Technol Biomed Life Sci. 2011;879:3005–11.
doi: 10.1016/j.jchromb.2011.08.037
Walker DK, Ackland MJ, James GC, Muirhead GJ, Rance DJ, Wastall P, et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica. 1999;29:297–310.
doi: 10.1080/004982599238687
Cho YS, Noh YH, Lim HS, Cho SH, Ghim JL, Choe S, et al. Effects of renal impairment on the pharmacokinetics and safety of udenafil. J Clin Pharmacol. 2018;58:905–12.
doi: 10.1002/jcph.1095
Ji HY, Lee HW, Kim HH, Kim DS, Yoo M, Kim WB, et al. Role of human cytochrome P450 3A4 in the metabolism of DA-8159, a new erectogenic. Xenobiotica. 2004;34:973–82.
doi: 10.1080/00498250400010898
Shim HJ, Kim YC, Lee JH, Park KJ, Kwon JW, Kim WB, et al. Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159, a new erectogenic, to mice, rats, rabbits, dogs and humans. Biopharm Drug Dispos. 2005;26:161–6.
doi: 10.1002/bdd.444
Zhu YT, Li L, Deng P, Chen XY, Zhong DF. Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J Pharm Biomed Anal. 2016;117:217–26.
doi: 10.1016/j.jpba.2015.09.001
Liu Y, Shao SG, Song HL, Yao XT, Liu J, Liu HZ, et al. Simultaneous determination of TPN729 and its five metabolites in human plasma and urine by liquid chromatography coupled to tandem mass spectrometry. J Pharm Biomed Anal. 2018;151:91–105.
doi: 10.1016/j.jpba.2017.12.057
Gao ZW, Zhu YT, Yu MM, Zan B, Liu J, Zhang YF, et al. Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model. Acta Pharmacol Sin. 2015;36:1528–36.
doi: 10.1038/aps.2015.118
Zhu YT. Study on the metabolism, pharmacokinetics, drug-drug interaction, and multidrug resistance revesal effect of TPN729. Dissertation, Chineses Academy of Science University. Beijing, 2017.
Wang Z, Jiang XR, Zhang XL, Tian GH, Yang RL, Wu JZ, et al. Pharmacokinetics-driven optimization of 4(3H)-pyrimidinones as phosphodiesterase type 5 inhibitors leading to TPN171, a clinical candidate for the treatment of pulmonary arterial hypertension. J Med Chem. 2019;62:4979–90.
doi: 10.1021/acs.jmedchem.9b00123
Zhou X, Gao ZW, Meng J, Chen XY, Zhong DF. Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs. Acta Pharmacol Sin. 2013;34:1420–6.
doi: 10.1038/aps.2013.76
Mi JQ, Zhao MM, Yang S, Jia YF, Wang Y, Wang BL, et al. Identification of cytochrome P450 isoforms involved in the metabolism of Syl930, a selective S1PR(1) agonist acting as a potential therapeutic agent for autoimmune encephalitis. Drug Metab Pharmacokinet. 2017;32:53–60.
doi: 10.1016/j.dmpk.2016.07.002
Wang P, Zhao YL, Zhu YD, Sun JB, Yerke A, Sang SM, et al. Metabolism of dictamnine in liver microsomes from mouse, rat, dog, monkey, and human. J Pharm Biomed Anal. 2016;119:166–74.
doi: 10.1016/j.jpba.2015.11.016
Sasahara K, Shimokawa Y, Hirao Y, Koyama N, Kitano K, Shibata M, et al. Pharmacokinetics and metabolism of delamanid, a novel anti-tuberculosis drug, in animals and humans: importance of albumin metabolism in vivo. Drug Metab Dispos. 2015;43:1267–76.
doi: 10.1124/dmd.115.064527
Li L, Chen XY, Zhou JL, Zhong DF. In vitro studies on the oxidative metabolism of 20(S)-ginsenoside Rh2 in human, monkey, dog, rat, and mouse liver microsomes, and human liver S9. Drug Metab Dispos. 2012;40:2041–53.
doi: 10.1124/dmd.112.046995
Cui YL, Tian XG, Ning J, Wang C, Yu ZL, Wang Y, et al. Metabolic profile of 3-acetyl-11-keto-beta-boswellic acid and 11-keto-beta-boswellic acid in human preparations in Vitro, species differences, and bioactivity variation. AAPS J. 2016;18:1273–88.
doi: 10.1208/s12248-016-9945-7
Fashe MM, Juvonen RO, Petsalo A, Rasanen J, Pasanen M. Species-specific differences in the in vitro metabolism of lasiocarpine. Chem Res Toxicol. 2015;28:2034–44.
doi: 10.1021/acs.chemrestox.5b00253
Faeste CK, Ivanova L, Uhlig S. In vitro metabolism of the mycotoxin enniatin B in different species and cytochrome P450 enzyme phenotyping by chemical inhibitors. Drug Metab Dispos. 2011;39:1768–76.
doi: 10.1124/dmd.111.039529
Martignoni M, Groothuis GMM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug MetabToxicol. 2006;2:875–94.
doi: 10.1517/17425255.2.6.875
Uehara S, Uno Y, Nakanishi K, Ishii S, Inoue T, Sasaki E, et al. Marmoset cytochrome P450 3A4 ortholog expressed in liver and small-intestine tissues efficiently metabolizes midazolam, alprazolam, nifedipine, and testosterone. Drug Metab Dispos. 2017;45:457–67.
doi: 10.1124/dmd.116.074898
Uehara S, Murayama N, Nakanishi Y, Zeldin DC, Yamazaki H, Uno Y. Immunochemical detection of cytochrome P450 enzymes in liver microsomes of 27 cynomolgus monkeys. J Pharmacol Exp Ther. 2011;339:654–61.
doi: 10.1124/jpet.111.185009
Ohtsuka T, Yoshikawa T, Kozakai K, Tsuneto Y, Uno Y, Utoh M, et al. Alprazolam as an in vivo probe for studying induction of CYP3A in cynomolgus monkeys. Drug Metab Dispos. 2010;38:1806–13.
doi: 10.1124/dmd.110.032656
Muirhead GJ, Rance DJ, Walker DK, Wastall P. Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil citrate. Br J Clin Pharmacol. 2002;53:13S–20S.
doi: 10.1046/j.06-5251.2001.00028.x
Ku HY, Ahn HJ, Seo KA, Kim H, Oh M, Bae SK, et al. The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil. Drug Metab Dispos. 2008;36:986–90.
doi: 10.1124/dmd.107.020099
Schadt S, Bister B, Chowdhury SK, Funk C, Hop C, Humphreys WG, et al. A decade in the MIST: learnings from investigations of drug metabolites in drug development under the “Metabolites in Safety Testing” regulatory guidance. Drug Metab Dispos. 2018;46:865–78.
doi: 10.1124/dmd.117.079848
Jia L, Liu XD. The conduct of drug metabolism studies considered good practice (II): in vitro experiments. Curr Drug Metab. 2007;8:822–9.
doi: 10.2174/138920007782798207