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Coadministration of Fluvoxamine and Tolperisone in relation to CYP2D6 genotype
Clinical Therapeutics Methods and Results: Mice treated with filtered and evaporated aqueous extract (spongy layer) of Cocos nucifera (AECN) (10mg/kg, 30mg/kg, 90mg/kg p.o) and mice treated with glibenclamide (10mg per kg) significantly reduced the Streptozocin (STZ) – induced increase in blood sugar (Bg), Total Cholesterol (Tc), and Serum Triglyceride level (Tg). AECN at 90mg/kg manifested an hypolipidemic effects but effectively lowers the elevated plasma BG level in oral glucose tolerance test, while Glibenclamide showed a significant reduction in TC, BG, TG in Normoglycemic rats. The histopathological analysis of Pancreas and the Plasma insulin level revealed beneficial effects of AECN in protecting beta cells integrity. In mice treated with AECN (10mg/kg, 30mg/kg, 90mg/kg), and mice that are treated with fenofibrate 200mg/kg, the {HFD} associated rise in TC, TG were significantly reduced. The hypocholesterolemic effects of AECN appears more at 90mg/kg with significant decrease in VLDL and LDL Cholesterol and an elevation of HDL Cholesterol. The Phytochemical Screening and GC-MS analysis of AECN revealed that AECN contained alpha, beta amyrin, and Pyrazine. Conclusion: These findings reflect the potential antihyperglycemic and hypolipidemic effects of AECN and suggest that alpha, beta amyrin or Pyrazine) could be a lead compound for drug development effective in diabetes and atherosclerosis.
Analysis of bioequivalence studies: problems, ways of solution Research objective: The investigation of drugs bioequivalence is the main requirement of medical and biological control of generics in Russia. Materials and Methods: On the basis of Yaroslavl Clinical hospital № 2 103 bioequivalence studies (BE) were conducted at the period of 2011 – 2015, including 12% with replicative design. Among these studies 21 were foreign and 82 – domestic. Volunteers of both sexes were involved in BE studies in the amount of 1437 people. From 18 to 103 volunteers participated in each study, depending on the protocol design (it is possible to hospitalize 45 volunteers in one time). Results and discussion: The strict control over BE studies conducted by the Quality Department in accordance with SOPs. The results revealed some defects of a general type: improper preparation of protocols (31%), lack of protection of the subjects (19%), lack of definition of responsibilities of the researcher (28%), the allocation of responsibilities between the sponsor and the organizers of clinical studies (24%). Using of Yaroslavl bioanalytical laboratory, which is working according GLP rules, avoid the errors in the pharmacokinetic part of the study, incorrect statistical analysis. We are faced with the following problems: the prevalence of non-compliance patients - 4%, the high prevalence of adverse events in some studies up to 78%, different problems during bioanalytical part - 5%, the problems associated with the final report on the study - in 2%. The center has the experience of using the pharmocogenetics in BE studies to reduce sample size (CYP2C9, CYP2C19, CYP2D6). Conclusions: Some mistakes in planning of BE studies leads to decreasing of drug efficacy and safety, loss of confidence in generics and the rising of drug therapy cost in future.
Coadministration of Fluvoxamine and Tolperisone in relation to CYP2D6 genotype Y.H. Kim; S.H. Kim; J.Y. Byeon; H.J. Lee; Y. Lee; Y.J. Lee; and S.Y. Lee School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
e54
Introduction: Tolperisone, a piperidine derivate, is used to relieve spasticity of neurological origin and muscle spasm. CYP2D6 was identified as the key enzyme in the metabolism of tolperisone and CYP1A2 and CYP2C19 were also involved in the metabolism of tolperisone. Fluvoxamine is an antidepressants and known as one of CYP2C19 inhibitors. As CYP2D6 is very high polymorphic and causes large interindividual differences in drug response, we investigated the effects fluvoxamine, a CYP2C19 inhibitor, on the pharmacokinetic parameters of tolperisone. Material and Methods: Thirty healthy Korean subjects were volunteered and divided into three different groups according to CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 10), CYP2D6*wt/*10 (n = 10), and CYP2D6*10/*10 (n = 10). All subjects received a single oral dose of 150 mg tolperisone in the control phase after overnight fasting. Before study day (day 6), a 50 mg oral dose of fluvoxamine was administered once a day for five days. On day 6, subjects received a single oral dose of tolperisone one hour after the administration of fluvoxamine. Blood samples were collected up to 12 hours after drug administration, and plasma concentrations of tolperisone were determined by using liquid chromatography-tandem mass spectrometry system. Results: Cmax and AUCinf of tolperisone was significantly different in each group between control phase and study day (P < 0.01). On study day, Cmax increased by 3.6-fold, 2.0-fold, and 5.0-fold, respectively in the CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 group, compared to control phase. Also, apparent oral clearance (CL/F) of tolperisone on study day decreased by 74.2%, 72.0%, and 86.2%, respectively in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 group, compared to control phase Conclusions: Significant differences in the pharmacokinetics of tolperisone were observed after coadministration of fluvoxamine in relation to CYP2D6 genotype.
Coadministration of duloxetine and tolperisone in relation to CYP2C19 genotype in Korean subjects Y.H. Kim; S.H. Kim; J.Y. Byeon; H.J. Lee; Y. Lee; Y.J. Lee; and S.Y. Lee School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea Introduction: Tolperisone is a centrally acting muscle relaxant is prescribed for the treatment of muscle spasm. Tolperisone is predominantly biotransformed by CYP2D6, and to a lesser extent by CYP2C19 and CYP1A2. Duloxetine is a potent dual reuptake inhibitor of serotonin and norepinephrine and acts as an inhibitor of CYP2D6. As CYP2C19 is one of the most important polymorphic CYPs, the aim of study was to determine pharmacokinetic changes of tolperisone after coadministration of duloxetine according to CYP2C19 genotype. Material and Methods: Twenty four healthy Korean subjects were volunteered and classified into three different groups in relation to CYP2C19 genotype: CYP2C19EM (CYP2C19*1/*1, n = 9), CYP2C19IM (CYP2C19*1/*2 or CYP2C19*1/*3, n = 8) and CYP2C19PM (CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3, n = 7). In the control phase, all subjects received a single 150 mg oral dose of tolperisone after overnight fasting. After administration of 30 mg duloxetine twice in a day for consecutive three days, 150 mg oral dose of tolperisone was administered one hour after administration of a single 30 mg oral dose of duloxetine in test phase. Blood samples were collected up to 12 hours after drug administration, and plasma concentrations of tolperisone were determined by using liquid chromatography-tandem mass spectrometry system.
Volume 37 Number 8S
Analysis of bioequivalence studies: problems, ways of solution Research objective: The investigation of drugs bioequivalence is the main requirement of medical and biological control of generics in Russia. Materials and Methods: On the basis of Yaroslavl Clinical hospital № 2 103 bioequivalence studies (BE) were conducted at the period of 2011 – 2015, including 12% with replicative design. Among these studies 21 were foreign and 82 – domestic. Volunteers of both sexes were involved in BE studies in the amount of 1437 people. From 18 to 103 volunteers participated in each study, depending on the protocol design (it is possible to hospitalize 45 volunteers in one time). Results and discussion: The strict control over BE studies conducted by the Quality Department in accordance with SOPs. The results revealed some defects of a general type: improper preparation of protocols (31%), lack of protection of the subjects (19%), lack of definition of responsibilities of the researcher (28%), the allocation of responsibilities between the sponsor and the organizers of clinical studies (24%). Using of Yaroslavl bioanalytical laboratory, which is working according GLP rules, avoid the errors in the pharmacokinetic part of the study, incorrect statistical analysis. We are faced with the following problems: the prevalence of non-compliance patients - 4%, the high prevalence of adverse events in some studies up to 78%, different problems during bioanalytical part - 5%, the problems associated with the final report on the study - in 2%. The center has the experience of using the pharmocogenetics in BE studies to reduce sample size (CYP2C9, CYP2C19, CYP2D6). Conclusions: Some mistakes in planning of BE studies leads to decreasing of drug efficacy and safety, loss of confidence in generics and the rising of drug therapy cost in future.
Coadministration of Fluvoxamine and Tolperisone in relation to CYP2D6 genotype Y.H. Kim; S.H. Kim; J.Y. Byeon; H.J. Lee; Y. Lee; Y.J. Lee; and S.Y. Lee School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
e54
Introduction: Tolperisone, a piperidine derivate, is used to relieve spasticity of neurological origin and muscle spasm. CYP2D6 was identified as the key enzyme in the metabolism of tolperisone and CYP1A2 and CYP2C19 were also involved in the metabolism of tolperisone. Fluvoxamine is an antidepressants and known as one of CYP2C19 inhibitors. As CYP2D6 is very high polymorphic and causes large interindividual differences in drug response, we investigated the effects fluvoxamine, a CYP2C19 inhibitor, on the pharmacokinetic parameters of tolperisone. Material and Methods: Thirty healthy Korean subjects were volunteered and divided into three different groups according to CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 10), CYP2D6*wt/*10 (n = 10), and CYP2D6*10/*10 (n = 10). All subjects received a single oral dose of 150 mg tolperisone in the control phase after overnight fasting. Before study day (day 6), a 50 mg oral dose of fluvoxamine was administered once a day for five days. On day 6, subjects received a single oral dose of tolperisone one hour after the administration of fluvoxamine. Blood samples were collected up to 12 hours after drug administration, and plasma concentrations of tolperisone were determined by using liquid chromatography-tandem mass spectrometry system. Results: Cmax and AUCinf of tolperisone was significantly different in each group between control phase and study day (P < 0.01). On study day, Cmax increased by 3.6-fold, 2.0-fold, and 5.0-fold, respectively in the CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 group, compared to control phase. Also, apparent oral clearance (CL/F) of tolperisone on study day decreased by 74.2%, 72.0%, and 86.2%, respectively in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 group, compared to control phase Conclusions: Significant differences in the pharmacokinetics of tolperisone were observed after coadministration of fluvoxamine in relation to CYP2D6 genotype.
Coadministration of duloxetine and tolperisone in relation to CYP2C19 genotype in Korean subjects Y.H. Kim; S.H. Kim; J.Y. Byeon; H.J. Lee; Y. Lee; Y.J. Lee; and S.Y. Lee School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea Introduction: Tolperisone is a centrally acting muscle relaxant is prescribed for the treatment of muscle spasm. Tolperisone is predominantly biotransformed by CYP2D6, and to a lesser extent by CYP2C19 and CYP1A2. Duloxetine is a potent dual reuptake inhibitor of serotonin and norepinephrine and acts as an inhibitor of CYP2D6. As CYP2C19 is one of the most important polymorphic CYPs, the aim of study was to determine pharmacokinetic changes of tolperisone after coadministration of duloxetine according to CYP2C19 genotype. Material and Methods: Twenty four healthy Korean subjects were volunteered and classified into three different groups in relation to CYP2C19 genotype: CYP2C19EM (CYP2C19*1/*1, n = 9), CYP2C19IM (CYP2C19*1/*2 or CYP2C19*1/*3, n = 8) and CYP2C19PM (CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3, n = 7). In the control phase, all subjects received a single 150 mg oral dose of tolperisone after overnight fasting. After administration of 30 mg duloxetine twice in a day for consecutive three days, 150 mg oral dose of tolperisone was administered one hour after administration of a single 30 mg oral dose of duloxetine in test phase. Blood samples were collected up to 12 hours after drug administration, and plasma concentrations of tolperisone were determined by using liquid chromatography-tandem mass spectrometry system.
Volume 37 Number 8S