Abstract
Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150 mg tolperisone with 240 mL of water, and blood samples were collected up to 12 h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher Cmax and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUCinf of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of CYP2C19 significantly affected tolperisone pharmacokinetics.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bae JW, Kim MJ, Park YS, Myung CS, Jang CG, Lee SY (2007) Considerable interindividual variation in the pharmacokinetics of tolperisone HCl. Int J Clin Pharmacol Ther 45(2):110–113. https://doi.org/10.5414/cpp45110
Bae JW, Oh KY, Yoon SJ, Shin HB, Jung EH, Cho CK, Lim CW, Kang P, Choi CI, Jang CG, Lee SY, Lee YJ (2020) Effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide. Arch Pharm Res 43(11):1207–1213. https://doi.org/10.1007/s12272-020-01293-4
Bajaj P, Arendt-Nielsen L, Madeleine P, Svensson P (2003) Prophylactic tolperisone for post-exercise muscle soreness causes reduced isometric force: a double-blind radomized crossover control study. Eur J Pain 7:407–418
Byeon JY, Lee JY, Jeon JS, Lee JE, Kim SH, Bae JW, Jang CG, Lee SY (2013) Pharmacokinetics of tolperisone in relation to CYP2C19 genotypes. Clinical Therapeutics 35(8):e54. https://doi.org/10.1016/j.clinthera.2013.07.147
Cho CK, Kang P, Park HJ, Lee YJ, Bae JW, Jang CG, Lee SY (2021a) Physiologically based pharmacokinetic (PBPK) modelling of tamsulosin related to CYP2D6*10 allele. Arch Pharm Res 44(11):1037–1049. https://doi.org/10.1007/s12272-021-01357-z
Cho CK, Park HJ, Kang P, Moon S, Lee YJ, Bae JW, Jang CG, Lee SY (2021b) Physiologically based pharmacokinetic (PBPK) modeling of meloxicam in different CYP2C9 genotypes. Arch Pharm Res 44(12):1076–1090. https://doi.org/10.1007/s12272-021-01361-3
Cho CK, Kang P, Park HJ, Ko E, Mu CY, Lee YJ, Choi CI, Kim HS, Jang CG, Bae JW, Lee SY (2022) Physiologically based pharmacokinetic (PBPK) modeling of piroxicam with regard to CYP2C9 genetic polymorphism. Arch Pharm Res 45(5):352–366. https://doi.org/10.1007/s12272-022-01388-0
Cho CK, Byeon JY, Kang P, Park JI, Jang CG, Lee SY, Choi CI, Nae JW, Lee J (2023) Effects of CYP2D6*10 allele on the pharmacokinetics of tolperisone. Arch Pharm Res 46(1) in press. https://doi.org/10.1007/s12272-022-01422-1
Choi CI, Park JI, Lee HI, Lee YJ, Jang CG, Bae JW, Lee SY (2012) Determination of tolperisone in human plasma by liquid chromatography/tandem mass spectrometry for clinical application. J Chromatogr B Analyt Technol Biomed Life Sci 911:59–63. https://doi.org/10.1016/j.jchromb.2012.10.027
Choi CI, Bae JW, Lee YJ, Lee HI, Jang CG, Lee SY (2014) Effects of CYP2C19 genetic polymorphisms on atomoxetine pharmacokinetics. J Clin Psychopharmacol 34(1):139–142. https://doi.org/10.1097/JCP.0b013e3182a608a2
Dalmadi B, Leibinger J, Szeberényi S, Borbás T, Farkas S, Szombathelyi Z, Tihanyi K (2003) Identification of metabolic pathways involved in the biotransformation of tolperisone by human microsomal enzymes. Drug Metab Dispos 31(5):631–636. https://doi.org/10.1124/dmd.31.5.631
de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994a) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269:15419–15422
de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994b) Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 46:594–598
Fukuda H, Watanabe K, Kudo Y, Oshima T, Ito T (1970) Pharmacological studies on a centrally acting muscle relaxant, 2,4’-dimethyl-3-piperidinopropiophenone, Mydocalm. Pharmacometrics 4:125–130
Jung EH, Lee CM, Byeon JY, Shin HB, Oh KY, Cho CK, Lim CW, Jang CG, Lee SY, Lee YJ (2020a) Relationship between plasma exposure of zolpidem and CYP2D6 genotype in healthy Korean subjects. Arch Pharm Res 43(9):976–981. https://doi.org/10.1007/s12272-020-01250-1
Jung EH, Lee YJ, Kim DH, Kang P, Lim CW, Cho CK, Jang CG, Lee SY, Bae JW (2020b) Effects of paroxetine on the pharmacokinetics of atomoxetine and its metabolites in different CYP2D6 genotypes. Arch Pharm Res 43(12):1356–1363. https://doi.org/10.1007/s12272-020-01300-8
Jung EH, Cho CK, Kang P, Park HJ, Lee YJ, Bae JW, Choi CI, Jang CG, Lee SY (2021) Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients. Arch Pharm Res 44(12):1109–1119. https://doi.org/10.1007/s12272-021-01363-1
Kamiya C, Inui N, Hakamata A, Miyakawa S, Tanaka S, Uchida S, Namiki N, Odagiri K, Watanabe H (2019) Effect of co-administered inducer or inhibitor on omeprazole pharmacokinetics based on CYP2C19 genotype. J Pharmacol Sci 139(4):361–366. https://doi.org/10.1016/j.jphs.2019.03.001
Karaźniewicz-Łada M, Danielak D, Rubiś B, Burchardt P, Oszkinis G, Główka F (2014) The influence of genetic polymorphism of Cyp2c19 isoenzyme on the pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases. J Clin Pharmacol 54(8):874–880. https://doi.org/10.1002/jcph.323
Kim YH, Kang P, Cho CK, Jung EH, Park HJ, Lee YJ, Bae JW, Jang CG, Lee SY (2021) Physiologically based pharmacokinetic (PBPK) modeling for prediction of celecoxib pharmacokinetics according to CYP2C9 genetic polymorphism. Arch Pharm Res 44(7):713–724. https://doi.org/10.1007/s12272-021-01346-2
Kim NT, Cho CK, Kang P, Park HJ, Lee YJ, Bae JW, Jang CG, Lee SY (2022) Effects of CYP2C9*3 and *13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects. Arch Pharm Res 45(2):114–121. https://doi.org/10.1007/s12272-021-01366-y
Kocsis P, Farkas S, Fodor L, Bielik N, Thán M, Kolok S, Gere A, Csejtei M, Tarnawa I (2005) Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage-gated sodium and calcium channels. J Pharmacol Exp Ther 315(3):1237–1246. https://doi.org/10.1124/jpet.105.089805
Lee HI, Byeon JY, Kim YH, Lee CM, Choi CI, Jang CG, Bae JW, Lee YJ, Lee SY (2018) Effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its active metabolites. Eur J Clin Pharmacol 74(11):1417–1426. https://doi.org/10.1007/s00228-018-2522-5
Lee CM, Kang P, Cho CK, Park HJ, Lee YJ, Bae JW, Choi CI, Kim HS, Jang CG, Lee SY (2022) Physiologically based pharmacokinetic modelling to predict the pharmacokinetics of metoprolol in different CYP2D6 genotypes. Arch Pharm Res 45(6):433–445. https://doi.org/10.1007/s12272-022-01394-2
Martos V, Hofer KE, Rauber-Lüthy C, Schenk-Jaeger KM, Kupferschmidt H, Ceschi A (2015) Acute toxicity profile of tolperisone in overdose: observational poison centre-based study. Clin Toxicol (phila) 53(5):470–476. https://doi.org/10.3109/15563650.2015.1022896
Miskolczi P, Vereczkey L, Frenkl R (1987) Gas-liquid chromatographic method for the determination of tolperisone in human plasma: pharmacokinetic and comparative bioavailability studies. J Pharm Biomed Anal 5(7):695–700. https://doi.org/10.1016/0731-7085(87)80082-1
Na JY, Jeon I, Yoon J, Choi Y, Yoon SH, Yu KS, Chung JY (2021) Influence of CYP2C19 polymorphisms on the pharmacokinetics of omeprazole in elderly subjects. Clin Pharmacol Drug Dev 10(12):1469–1477. https://doi.org/10.1002/cpdd.966
Pawlowska M, Bogiel M, Duda J, Sieradzki E (2015) Influence of CYP2D6 and CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy volunteers. Eur J Clin Pharmacol 71(6):699–705. https://doi.org/10.1007/s00228-015-1856-5
Shin HB, Jung EH, Kang P, Lim CW, Oh KY, Cho CK, Lee YJ, Choi CI, Jang CG, Lee SY, Bae JW (2020) ABCB1 c.2677G>T/c.3435C>T diplotype increases the early-phase oral absorption of losartan. Arch Pharm Res 43(11):1187–1196. https://doi.org/10.1007/s12272-020-01294-3
Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79(1):103–113. https://doi.org/10.1016/j.clpt.2005.10.002
Song C, Li X, Mao P, Song W, Liu L, Zhang Y (2022) Impact of CYP2C19 and CYP2C9 gene polymorphisms on sodium valproate plasma concentration in patients with epilepsy. Eur J Hosp Pharm 29(4):198–201. https://doi.org/10.1136/ejhpharm-2020-002367
Vora A (2010) Tolperisone. J Assoc Physicians India 58:127–128
Whang SS, Cho CK, Jung EH, Kang P, Park HJ, Lee YJ, Choi CI, Bae JW, Kim HS, Jang CG, Lee SY (2022) Physiologically based pharmacokinetic (PBPK) modeling of flurbiprofen in different CYP2C9 genotypes. Arch Pharm Res 45(8):584–595. https://doi.org/10.1007/s12272-022-01403-4
Zhang HJ, Zhang XH, Liu J, Sun LN, Shen YW, Zhou C, Zhang HW, Xie LJ, Chen J, Liu Y, Wang YQ (2020) Effects of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of proton pump inhibitors. Pharmacol Res 152:104606. https://doi.org/10.1016/j.phrs.2019.104606
Acknowledgements
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning (NRF-2019R1A2C1004582) and the grant from Ministry of Food and Drug Safety.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Cho, C., Byeon, JY., Kang, P. et al. Effects of CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy subjects. Arch. Pharm. Res. 46, 111–116 (2023). https://doi.org/10.1007/s12272-022-01423-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-022-01423-0