The Effects Of CYP2D6 Gene Polymorphism、gender And High-fat Diet On The Pharmacokinetics Of Paroxetine Mesylate In Healthy People Of Chinese

Objective:To investigate the effects of CYP2D6 gene polymorphism、gender and high-fat diet on the pharmacokinetics of Paroxetine Mesylate in Han healthy people of Chinese; while establishing the methods of LC-MS / MS of Paroxetine plasma concentrations. Methods:Henan Han healthy volunteers were randomly assigned to the fasting group(48 people, including 30 men, 18 women) and high-fat diet group(48 people, including 32 men, 16 women), the genotype of the above subjects were detected by PCR-RFLP. Every group was given a single oral dose of Paroxetine Mesylate capsule, blood samples were collected at different time points until 120 h. The concentrations of paroxetine in blood were measured by LC-MS/MS method, while the pharmacokinetics of them was analyzed, and drawing the drug-time curve at the same time. Results:The high-fat group, there were 18 people with CYP2D6 * 1 / * 1, including 12 men and 6 women; 27 people with CYP2D6 * 1 / * 10, including 17 men and 10 women; CYP2D6 * 10 / * 10 genotypes including 3 men, and 0 women in high-fat group. In fasting group, there were 14 people with CYP2D6 * 1 / * 1, including 9 men and 5 women; 34 people with CYP2D6 * 1 / * 10, including 21 men and 13 women; CYP2D6 * 10 / * 10 genotypes was not founded in fasting group.The first: the results of the effects of Genetic polymorphism on pharmacokinetic showed that:1. In the males of the high-fat group, compared with the CYP2D6*1/*1 subjects, tmax、t1/2 of the subjects with CYP2D6*1/*10 had no significant difference(Z=-1.545、-0.823,P>0.05), CL(F)、 Vd decreased obviously(Z=-3.454,-3.321,P<0.01), ρmax、AUC0-120、AUC0-∞ increased obviously(Z=-3.365、-3.454、-3.454,P<0.01).2. In the females of the high-fat group, compared with the CYP2D6*1/*1 subjects, tmax、t1/2 of the subjects with CYP2D6*1/*10 had no significant difference(t=-1.408,Z=-1.735,P>0.05), CL(F)、Vd decreased obviously(Z=-3.254,Z=-3.037,P<0.05), ρmax、AUC0-120、AUC0-∞ increased obviously(t=-5.232、-4.688、-4.692,P<0.05). 3. In the males of the fasting group, compared with the CYP2D6*1/*1 subjects, tmax、t1/2 of the subjects with CYP2D6*1/*10 had no significant difference((Z=-1.145、t=1.400,P>0.05), CL(F)、Vd decreased obviously(Z=-2.557、-2.104,P<0.05), ρmax、AUC0-120、AUC0-∞ increased obviously(Z=-2.421、-2.512、-2.557,P<0.05).4. In the females of the fasting group, compared with the CYP2D6*1/*1 subjects, tmax、ρmax、Vd 、t1/2 of the subjects with CYP2D6*1/*10 had no significant difference(Z=-1.921、-1.922,t=1.905、-2.117,P>0.05), CL(F) decreased obviously(Z=-2.162,P<0.05), AUC0-120、AUC0-∞ increased obviously(Z=-2.021、-2.021,P<0.05).The second: the results of the effects of gender on pharmacokinetic showed that:1. In the fasting group of the CYP2D6*1/*1, t1/2、CL(F)、Vd、tmax、ρmax、AUC0-120 and AUC0-∞ showed no significant difference between males and females(t=0.486、1.578、-1.969,Z=-1.237、-0.867、-1.267、-1.267,P>0.05);2. In the high-fat group of the CYP2D6*1/*1, tmax、ρmax、CL(F) 、Vd、AUC0-120、AUC0-∞ and t1/2 showed no significant difference between males and females(Z=0.000、-1.499、-1.499、-1.499、-1.499、-1.499,t=-0.624,P>0.05);3. In the fasting group of the CYP2D6*1/*10, tmax(Z=-2.221,P<0.05)showed some differences, t1/2、ρmax、CL(F)、Vd、AUC0-120 and AUC0-∞ showed no significant difference between males and females(t=-0.332,Z=-0.478、-0.851、-0.656、-0.833、-0.868,P>0.05);4. In the high-fat group of the CYP2D6*1/*10, CL(F)(Z=-2.775,P<0.05)showed some differences, Vd、 tmax、ρmax、 t1/2 、AUC0-120 and AUC0-∞ showed no significant difference between males and females(t=-1.506、Z=-0.969、-1.556、-0.954、-1.607、-1.607,P>0.05);The third: the results of the effects of high-fat diet on pharmacokinetic showed that:1. In the males of the CYP2D6*1/*1, t1/2、CL(F)、Vd 、tmax、ρmax、AUC0-120 and AUC0-∞ showed no significant difference between fasting and high-fat group(t=-0.584、1.448、1.302,Z=-1.419、-1.421、-1.492、-1.421,P>0.05);2. In the females of the CYP2D6*1/*1, tmax、CL(F)、Vd、ρmax、t1/2 、AUC0-120 and AUC0-∞ showed no significant difference between fasting and high-fat group(Z=-0.106、-1.278、-1.278,t=1.832、-0.493、-1.100、-1.094,P>0.05).3. In the males of the CYP2D6*1/*10, t1/2 、tmax、ρmax、CL(F)、 Vd 、AUC0-120 and AUC0-∞ showed no significant difference between fasting and high-fat group(t=0.479,Z=-1.546、-1.365、-1.366、-1.248、-1.366、-1.366,P>0.05);4. In the females of the CYP2D6*1/*10, Vd、ρmax、tmax、t1/2 、CL(F)、AUC0-120 and AUC0-∞ showed no significant difference between fasting and high-fat group(t=-1.674、Z=-1.923、-0.545、-0.062、-1.426、-1.426、-1.426,P>0.05)。 Conclusion:The mutation CYP2D6*10 could lead to the metabolic phenotype changes of paroxetine mesylate in Henan Han healthy subjects, gender and high-fat showed no effects on the metabolic of paroxetine mesylate in Henan Han healthy subjects.