文拉法辛在中国健康人群中的立体选择性代谢研究
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摘要
一、目的
建立文拉法辛及其代谢产物氧去甲基文拉法辛的手性拆分方法,研究文拉法辛及其代谢产物氧去甲基文拉法辛手性异构体的单剂量药动学,并初步探讨文拉法辛在中国不同的CYP2D6*10等位基因型健康人群中的立体选择性代谢机制,为深入研究文拉法辛药动学及其代谢机制提供参考,并为进一步的临床治疗方案提供依据。
二、方法
招募88名汉族健康受试者,采用RFLP-PCR法进行基因分型,筛选其中12名符合要求的受试者进行文拉法辛单剂量药代动力学研究。第一周期单次服用文拉法辛75mg,第二周期单次服用文拉法辛75 mg+苯海拉明25 mg,于设定的时间点采血4 mL,经适当处理后测定文拉法辛及其主要代谢产物氧去甲基文拉法辛对映异构体的血药浓度。
本研究实验设计原则:随机,对照,开放性。
1.RFLP-PCR法对健康人群CYP2D6*10等位基因进行分型
1.1 DNA提取
采用经典的酚-氯仿抽提法对人全血中的DNA进行提取。
1.2 RFLP-PCR法进行基因分型
用经典的RFLP-PCR法对88名健康受试者的基因进行分型,筛选出12名符合要求的受试者进行文拉法辛单剂量药代动力学实验。
2.本部分实验中所涉及的测定方法
2.1用Chirobiotic V手性柱拆分VEN与ODV手性异构体。
2.2 HPLC-MS/MS法测定体内VEN与ODV手性异构体血药浓度。
三、结果
1.VEN与ODV手性异构体的拆分
建立了VEN与ODV手性异构体的拆分方法,以92%甲醇为有机相,以30 mM的醋酸铵为水相,较好地拆分了VEN与ODV手性异构体;VEN:分离度1.12,分离因子1.7;ODV:分离度1.18,分离因子1.6。
2.生物样本测定
用HPLC-MS/MS法测定VEN与ODV手性异构体血药浓度。S-VEN,R-VEN,S-ODV,R-ODV分别在0.28～423.00μg·L~(-1)、0.28～423.00μg·L~(-1)、0.35～532.80μg·L~(-1)和0.35～532.80μg·L~(-1)浓度范围线性良好。方法回收率均在77.7%～110.7%范围内,日内和日间RSD皆小于11.0%。
3.VEN与ODV手性异构体单剂量药代动力学
本课题首次获得了VEN手性异构体在中国健康人群中的单剂量药代动力学资料,并对VEN在不同CYP2D6*10等位基因人群中的立体选择性代谢进行了初步研究。
所测样本的药动学参数如下:R-VEN与S-VEN的AUC_((0-∞))分别为516.6±273.2和769.4±259.0μg·h·L~(-1),C_(max)分别为33.1±17.7和48.1±15.9μg·L~(-1),t_(1/2)分别为11.8±4.2和8.7±1.9 h,t_(max)分别为2.3±0.9,2.5±0.9h。R-ODV与S-ODV的AUC_((0-∞))分别为913.3±265.8和868.4±336.7μg·h·L~(-1),C_(max)分别为40.5±18.0和50.2±24.9μg·L~(-1),t_(1/2)分别为14.4±5.6和16.6±8.3h,t_(max)分别为16.6±8.3,14.4±5.6 h。
S-VEN与R-VEN在AUC_((0-∞)),t_(1/2),t_(max),k_a与k_e上存在有显著性差异(P＜0.05),而R-ODV与S-ODV仅在t_(1/2),t_(max)与k_e上存在有显著性差异(P＜0.05),AUC_((0-∞))无差异。在C_(max)值上,S-VEN＞R-VEN,S-ODV＞R-ODV并且两两之间都存在有显著性差异(P＜0.05)。
4.苯海拉明和VEN的药物相互作用
健康受试者合用苯海拉明前后,R-VEN、S-VEN、R-ODV、S-ODV四个物质的AUC_((0-∞))值都有明显的上升,主要原因是BEZ抑制了CYP2D6酶,R-VEN与S-VEN的代谢减少,其AUC_((0-∞))值增加,而R-ODV与S-ODV的AUC_((0-∞))值增加则是由于CYP2D6酶被部分抑制后R-ODV与S-ODV通过其二次代谢生成另一代谢产物DDV减少。这四个被分析物中尤以R-ODV与S-ODV的增加最为显著(p＜0.05)。进一步将VEN与ODV手性异构体的AUC_((0-∞))值进行分析发现,S-ODV的AUC/S-VEN的AUC与R-ODV的AUC/R-VEN的AUC这两个比值在未服用BEZ时无显著性差异,而在服用BEZ后两者之间存在有显著性差异(P＜0.05)。
对参数C_(max)进行比较发现,除S-ODV外,其余三个物质在合用BEZ后C_(max)值都增加,其中尤以S-VEN、R-ODV增加最显著(P＜0.05)。在对其它两个重要的药动学参数t_(1/2)与t_(max)进行分析时发现,R-VEN与S-VEN的t_(max)减小了,说明两者的达峰时间缩短了,而R-ODV与S-ODV则得到了不同的结果,S-ODV的t_(max)值增加,而R-ODV的t_(max)值减少,并且R-ODV在服用BEZ前后t_(max)值产生了显著的统计学差异(P＜0.05)。而参数t_(1/2)在服用BEZ前后的改变很小,R-VEN、S-VEN的t_(1/2)减小,而R-ODV、S-ODV的t_(1/2)则上升,且S-ODV合用前后产生了显著性差异(P＜0.05)。以上几点说明CYP2D6对R-VEN、S-VEN代谢生成R-ODV、S-ODV存在有选择性。
5.CYP2D6*10对VEN与ODV手性异构体药动学的影响
CYP2D6*10等位基因对VEN手性异构体代谢产生影响,虽然CYP2D6*10/*10组与CYP2D6*1/*1组的药动学参数在统计学上无显著性差异,但是CYP2D6*10/*10组的C_(max)与AUC要高于CYP2D6*1/*1组,而CYP2D6*10等位基因对VEN两个旋光异构体的代谢无区别。
四、结论
1.在中国健康受试者中,VEN手性异构体药动学符合一室模型且VEN与ODV手性异构体在代谢环节上存在有较大差异。
2.单剂量服用苯海拉明,可抑制文拉法辛的代谢,但其对S-VEN代谢的抑制作用更强,说明文拉法辛代谢存在立体选择性差异。
3.文拉法辛与苯海拉明合用产生明显的药物动力学相互作用,其原因是苯海拉明抑制体内CYP2D6活性。CYP2D6活性下降后,VEN手性异构体的峰浓度明显增加,AUC有上升趋势,主要原因是CYP2D6活性下降,VEN手性异构体经CYP2D6代谢减少。因此,其C_(max)与AUC都有所上升。而ODV手性异构体C_(max)与AUC值的增加可能源于ODV需要经CYP2D6二次代谢生成另一代谢产物DDV,CYP2D6活性下降后,其二次代谢减少,因此这两个参数都表现出上升的趋势。
4.CYP2D6*10对VEN与ODV手性异构体的代谢产生影响,虽然无统计学的显著性差异,但是主要原因是样本量较小,而且本实验为单剂量药动学研究,CYP2D6*10对药物的代谢差异未充分显露出来。
OBJECTIVES
To estabolish a method for the chiral separation of venlafaxine and O-desmethylvenlafaxine,to study the single dose pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine enantiomers and to study the enantiomeric metabolic mechanism of venlafaxine.To study the stereoselective mechanism of venlafaxine in the Chinese CYP2D6~* 10 allele volunteers.
METHODS
We recruited 88 Chinese healthyl volunteers.The CYP2D6~*10 genotype of them were determinated by using the RFLP-PCR.Twelve subjects were recruited again to participate into the following pharmacokinetic study of VEN.There were two periods in this research. The subjects were administered 75 mg VEN at the first period and 75 mg venlafaxine and 25 mg benzhydramine at the second period.Blood samples of VEN and ODV were collected before and at 0.5,1.0,1.5,2,3, 4,6,8,10.0,12.0,15.0,24.0 and 36.0 h after the oral administration of VEN at 8:00 AM.Plasma was stored at -80℃to determination.The VEN and ODV enantiomers were determinated by using the method which we have set up in this paper.
1.RFLP-PCR determinate the CYP2D6~* 10 allele genotype in the healthy volunteers
1.1 DNA extract
The DNA was taken from the whole blood by using the penol—chloroform method.
1.2 RFLP-PCR determinate the CYP2D6~* 10 allele
2.Analytic methods in this study
2.1 Chiral solid phase method for the chiral separation of VEN and ODV.
2.2 HPLC-MS/MS method for the determination of VEN and ODV enantiomers.
RESULTS
1.Chiral separation of VEN and ODV
A method for the enantiomeric determination of VEN and ODV was estabolished.With 92%methol as organic phase and 30 mM ammonium acetate as buffer,VEN and ODV enantiomers were separated well; resolution factor was 1.70,1.60 and separation factor was 1.12,1.18 for VEN and ODV respectively。
2.Determination of VEN and ODV enantiomers
VEN and ODV enantiomers were determined by chiral method.The calibration curves were linear in the ranges of 0.28～423.00μg·L~(-1)for S-VEN,0.28～423.00μg·L~(-1)for R-VEN,0.35～532.80μg·L~(-1)for S-ODV and 0.35～532.80μg·L~(-1)for R-ODV.The methodology recoveries were all in the range of 77.70%～110.67%.The intra-day and inter-day RSD were less than 11%.
3.The single dose pharmacokinetics of VEN and ODV enantiomers
It's the first time to acquire the pharmacokinetic information of VEN enantiomers in the Chinese healthy volunteers and study the VEN stereoselective metabolism in the Chinese with CYP2D6~* 10 allele.
The pharmacokinetic parameters were listed on following:the AUC_((0-∞))of R-VEN and S-VEN were 516.6±273.2 and 769.4±259.0μg·h·L~(-1),C_(max)were 33.1±17.7 and 48.1±15.9μg·L~(-1),t_(1/2)were 11.7±4.1 and 8.7±2.0 h,t_(max)were 2.3±0.9,2.5±0.9h,respectively.While the AUC_((0-∞))of R-ODV and S-ODV were 913.3±265.8 and 868.4±336.7μg·h·L~(-1),C_(max)were 40.5±18.0 and 50.2±24.9μg·L~(-1),t_(1/2)were 14.4±5.6 and 16.6±8.3 h,t_(max)were 16.6±8.3,14.4±5.6 h,respectively.
There were great differences between S-VEN and R-VEN in the AUC_((0-∞))t_(1/2),t_(max),ka and ke(P＜0.05).While there were only great differences between the R-ODV and S-ODV in the t_(1/2),t_(max),ka and ke(P＜0.05).The S-VEN was more great than the R-VEN in C_(max).and there was great difference between them(P＜0.05).So were the R-ODV and S-ODV.
But for the AUC_((0-∞)),there were no great difference between R-ODV and S-ODV.
4.The interaction of pharmacokinetics between BEZ and VEN
After the BEZ and VEN were co-administered,the AUC_((0-∞))of the R-VEN,S-VEN,R-ODV and S-ODV increased significantly,the main reason was that BEZ inhibited the CYP2D6,so the metabolism of R-VEN and S-VEN through the CYP2D6 reduced.While the increase of AUC_((0-∞)) of the R-ODV and S-ODV was due to the inhibition of CYP2D6,the metabolism of R-ODV and S-ODV to the R-DDV and S-DDV through the CYP2D6 reduced.The ratio of AUC_((0-∞))of the S-ODV to the S-VEN and the ratio of AUC_((0-∞))of the R-ODV to the R-VEN have no difference before the administration of BEZ,which have the great difference after the administration of BEZ(P＜0.05).
After the BEZ and VEN were co-administered,the C_(max)of R-VEN, S-VEN and R-ODV were increased,especially for the S-VEN and R-ODV(P＜0.05).While for the other two important parameters,the t_(max) of R-VEN and S-VEN reduced,while the R-ODV and S-ODV have different results,t_(max)of R-ODV increased(P＜0.05),S-ODV increased. The t_(1/2)of R-VEN and S-VEN reduced after co-administration of BEZ, while the t_(1/2)of R-ODV and S-ODV increased,especially for the S-ODV, there was great differences(P＜0.05).
So the CYP2D6 has the stereoselective metabolism for the R-VEN and S-VEN but for the R-ODV and S-ODV.
CONCLUSIONS
1.The VEN and ODV enantiomers have the great difference in the metabolism in Chinese healthy volunteers.
2.BEZ can inhibit the metabolism of VEN specifically to the S-ODV after single administration of BEZ.
3.BEZ can inhibt the CYP2D6,so co-administration of BEZ and VEN could have strong influence on the VEN pharmacokinetics.After being inhibited,the VEN enantiomers C_(max)and AUC increased.The possible reason is that the metabolism of VEN enantiomers by CYP2D6 deduced for the inhibition of CYP2D6.So the C_(max)and AUC of them increased greatly,while the raise of the C_(max)and AUC of ODV enantiomers is due to the inhibition of metabolism of ODV to DDV by by BEZ.
建立文拉法辛及其代谢产物氧去甲基文拉法辛的手性拆分方法,研究文拉法辛及其代谢产物氧去甲基文拉法辛手性异构体的单剂量药动学,并初步探讨文拉法辛在中国不同的CYP2D6*10等位基因型健康人群中的立体选择性代谢机制,为深入研究文拉法辛药动学及其代谢机制提供参考,并为进一步的临床治疗方案提供依据。
二、方法
招募88名汉族健康受试者,采用RFLP-PCR法进行基因分型,筛选其中12名符合要求的受试者进行文拉法辛单剂量药代动力学研究。第一周期单次服用文拉法辛75mg,第二周期单次服用文拉法辛75 mg+苯海拉明25 mg,于设定的时间点采血4 mL,经适当处理后测定文拉法辛及其主要代谢产物氧去甲基文拉法辛对映异构体的血药浓度。
本研究实验设计原则:随机,对照,开放性。
1.RFLP-PCR法对健康人群CYP2D6*10等位基因进行分型
1.1 DNA提取
采用经典的酚-氯仿抽提法对人全血中的DNA进行提取。
1.2 RFLP-PCR法进行基因分型
用经典的RFLP-PCR法对88名健康受试者的基因进行分型,筛选出12名符合要求的受试者进行文拉法辛单剂量药代动力学实验。
2.本部分实验中所涉及的测定方法
2.1用Chirobiotic V手性柱拆分VEN与ODV手性异构体。
2.2 HPLC-MS/MS法测定体内VEN与ODV手性异构体血药浓度。
三、结果
1.VEN与ODV手性异构体的拆分
建立了VEN与ODV手性异构体的拆分方法,以92%甲醇为有机相,以30 mM的醋酸铵为水相,较好地拆分了VEN与ODV手性异构体;VEN:分离度1.12,分离因子1.7;ODV:分离度1.18,分离因子1.6。
2.生物样本测定
用HPLC-MS/MS法测定VEN与ODV手性异构体血药浓度。S-VEN,R-VEN,S-ODV,R-ODV分别在0.28～423.00μg·L~(-1)、0.28～423.00μg·L~(-1)、0.35～532.80μg·L~(-1)和0.35～532.80μg·L~(-1)浓度范围线性良好。方法回收率均在77.7%～110.7%范围内,日内和日间RSD皆小于11.0%。
3.VEN与ODV手性异构体单剂量药代动力学
本课题首次获得了VEN手性异构体在中国健康人群中的单剂量药代动力学资料,并对VEN在不同CYP2D6*10等位基因人群中的立体选择性代谢进行了初步研究。
所测样本的药动学参数如下:R-VEN与S-VEN的AUC_((0-∞))分别为516.6±273.2和769.4±259.0μg·h·L~(-1),C_(max)分别为33.1±17.7和48.1±15.9μg·L~(-1),t_(1/2)分别为11.8±4.2和8.7±1.9 h,t_(max)分别为2.3±0.9,2.5±0.9h。R-ODV与S-ODV的AUC_((0-∞))分别为913.3±265.8和868.4±336.7μg·h·L~(-1),C_(max)分别为40.5±18.0和50.2±24.9μg·L~(-1),t_(1/2)分别为14.4±5.6和16.6±8.3h,t_(max)分别为16.6±8.3,14.4±5.6 h。
S-VEN与R-VEN在AUC_((0-∞)),t_(1/2),t_(max),k_a与k_e上存在有显著性差异(P＜0.05),而R-ODV与S-ODV仅在t_(1/2),t_(max)与k_e上存在有显著性差异(P＜0.05),AUC_((0-∞))无差异。在C_(max)值上,S-VEN＞R-VEN,S-ODV＞R-ODV并且两两之间都存在有显著性差异(P＜0.05)。
4.苯海拉明和VEN的药物相互作用
健康受试者合用苯海拉明前后,R-VEN、S-VEN、R-ODV、S-ODV四个物质的AUC_((0-∞))值都有明显的上升,主要原因是BEZ抑制了CYP2D6酶,R-VEN与S-VEN的代谢减少,其AUC_((0-∞))值增加,而R-ODV与S-ODV的AUC_((0-∞))值增加则是由于CYP2D6酶被部分抑制后R-ODV与S-ODV通过其二次代谢生成另一代谢产物DDV减少。这四个被分析物中尤以R-ODV与S-ODV的增加最为显著(p＜0.05)。进一步将VEN与ODV手性异构体的AUC_((0-∞))值进行分析发现,S-ODV的AUC/S-VEN的AUC与R-ODV的AUC/R-VEN的AUC这两个比值在未服用BEZ时无显著性差异,而在服用BEZ后两者之间存在有显著性差异(P＜0.05)。
对参数C_(max)进行比较发现,除S-ODV外,其余三个物质在合用BEZ后C_(max)值都增加,其中尤以S-VEN、R-ODV增加最显著(P＜0.05)。在对其它两个重要的药动学参数t_(1/2)与t_(max)进行分析时发现,R-VEN与S-VEN的t_(max)减小了,说明两者的达峰时间缩短了,而R-ODV与S-ODV则得到了不同的结果,S-ODV的t_(max)值增加,而R-ODV的t_(max)值减少,并且R-ODV在服用BEZ前后t_(max)值产生了显著的统计学差异(P＜0.05)。而参数t_(1/2)在服用BEZ前后的改变很小,R-VEN、S-VEN的t_(1/2)减小,而R-ODV、S-ODV的t_(1/2)则上升,且S-ODV合用前后产生了显著性差异(P＜0.05)。以上几点说明CYP2D6对R-VEN、S-VEN代谢生成R-ODV、S-ODV存在有选择性。
5.CYP2D6*10对VEN与ODV手性异构体药动学的影响
CYP2D6*10等位基因对VEN手性异构体代谢产生影响,虽然CYP2D6*10/*10组与CYP2D6*1/*1组的药动学参数在统计学上无显著性差异,但是CYP2D6*10/*10组的C_(max)与AUC要高于CYP2D6*1/*1组,而CYP2D6*10等位基因对VEN两个旋光异构体的代谢无区别。
四、结论
1.在中国健康受试者中,VEN手性异构体药动学符合一室模型且VEN与ODV手性异构体在代谢环节上存在有较大差异。
2.单剂量服用苯海拉明,可抑制文拉法辛的代谢,但其对S-VEN代谢的抑制作用更强,说明文拉法辛代谢存在立体选择性差异。
3.文拉法辛与苯海拉明合用产生明显的药物动力学相互作用,其原因是苯海拉明抑制体内CYP2D6活性。CYP2D6活性下降后,VEN手性异构体的峰浓度明显增加,AUC有上升趋势,主要原因是CYP2D6活性下降,VEN手性异构体经CYP2D6代谢减少。因此,其C_(max)与AUC都有所上升。而ODV手性异构体C_(max)与AUC值的增加可能源于ODV需要经CYP2D6二次代谢生成另一代谢产物DDV,CYP2D6活性下降后,其二次代谢减少,因此这两个参数都表现出上升的趋势。
4.CYP2D6*10对VEN与ODV手性异构体的代谢产生影响,虽然无统计学的显著性差异,但是主要原因是样本量较小,而且本实验为单剂量药动学研究,CYP2D6*10对药物的代谢差异未充分显露出来。
OBJECTIVES
To estabolish a method for the chiral separation of venlafaxine and O-desmethylvenlafaxine,to study the single dose pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine enantiomers and to study the enantiomeric metabolic mechanism of venlafaxine.To study the stereoselective mechanism of venlafaxine in the Chinese CYP2D6~* 10 allele volunteers.
METHODS
We recruited 88 Chinese healthyl volunteers.The CYP2D6~*10 genotype of them were determinated by using the RFLP-PCR.Twelve subjects were recruited again to participate into the following pharmacokinetic study of VEN.There were two periods in this research. The subjects were administered 75 mg VEN at the first period and 75 mg venlafaxine and 25 mg benzhydramine at the second period.Blood samples of VEN and ODV were collected before and at 0.5,1.0,1.5,2,3, 4,6,8,10.0,12.0,15.0,24.0 and 36.0 h after the oral administration of VEN at 8:00 AM.Plasma was stored at -80℃to determination.The VEN and ODV enantiomers were determinated by using the method which we have set up in this paper.
1.RFLP-PCR determinate the CYP2D6~* 10 allele genotype in the healthy volunteers
1.1 DNA extract
The DNA was taken from the whole blood by using the penol—chloroform method.
1.2 RFLP-PCR determinate the CYP2D6~* 10 allele
2.Analytic methods in this study
2.1 Chiral solid phase method for the chiral separation of VEN and ODV.
2.2 HPLC-MS/MS method for the determination of VEN and ODV enantiomers.
RESULTS
1.Chiral separation of VEN and ODV
A method for the enantiomeric determination of VEN and ODV was estabolished.With 92%methol as organic phase and 30 mM ammonium acetate as buffer,VEN and ODV enantiomers were separated well; resolution factor was 1.70,1.60 and separation factor was 1.12,1.18 for VEN and ODV respectively。
2.Determination of VEN and ODV enantiomers
VEN and ODV enantiomers were determined by chiral method.The calibration curves were linear in the ranges of 0.28～423.00μg·L~(-1)for S-VEN,0.28～423.00μg·L~(-1)for R-VEN,0.35～532.80μg·L~(-1)for S-ODV and 0.35～532.80μg·L~(-1)for R-ODV.The methodology recoveries were all in the range of 77.70%～110.67%.The intra-day and inter-day RSD were less than 11%.
3.The single dose pharmacokinetics of VEN and ODV enantiomers
It's the first time to acquire the pharmacokinetic information of VEN enantiomers in the Chinese healthy volunteers and study the VEN stereoselective metabolism in the Chinese with CYP2D6~* 10 allele.
The pharmacokinetic parameters were listed on following:the AUC_((0-∞))of R-VEN and S-VEN were 516.6±273.2 and 769.4±259.0μg·h·L~(-1),C_(max)were 33.1±17.7 and 48.1±15.9μg·L~(-1),t_(1/2)were 11.7±4.1 and 8.7±2.0 h,t_(max)were 2.3±0.9,2.5±0.9h,respectively.While the AUC_((0-∞))of R-ODV and S-ODV were 913.3±265.8 and 868.4±336.7μg·h·L~(-1),C_(max)were 40.5±18.0 and 50.2±24.9μg·L~(-1),t_(1/2)were 14.4±5.6 and 16.6±8.3 h,t_(max)were 16.6±8.3,14.4±5.6 h,respectively.
There were great differences between S-VEN and R-VEN in the AUC_((0-∞))t_(1/2),t_(max),ka and ke(P＜0.05).While there were only great differences between the R-ODV and S-ODV in the t_(1/2),t_(max),ka and ke(P＜0.05).The S-VEN was more great than the R-VEN in C_(max).and there was great difference between them(P＜0.05).So were the R-ODV and S-ODV.
But for the AUC_((0-∞)),there were no great difference between R-ODV and S-ODV.
4.The interaction of pharmacokinetics between BEZ and VEN
After the BEZ and VEN were co-administered,the AUC_((0-∞))of the R-VEN,S-VEN,R-ODV and S-ODV increased significantly,the main reason was that BEZ inhibited the CYP2D6,so the metabolism of R-VEN and S-VEN through the CYP2D6 reduced.While the increase of AUC_((0-∞)) of the R-ODV and S-ODV was due to the inhibition of CYP2D6,the metabolism of R-ODV and S-ODV to the R-DDV and S-DDV through the CYP2D6 reduced.The ratio of AUC_((0-∞))of the S-ODV to the S-VEN and the ratio of AUC_((0-∞))of the R-ODV to the R-VEN have no difference before the administration of BEZ,which have the great difference after the administration of BEZ(P＜0.05).
After the BEZ and VEN were co-administered,the C_(max)of R-VEN, S-VEN and R-ODV were increased,especially for the S-VEN and R-ODV(P＜0.05).While for the other two important parameters,the t_(max) of R-VEN and S-VEN reduced,while the R-ODV and S-ODV have different results,t_(max)of R-ODV increased(P＜0.05),S-ODV increased. The t_(1/2)of R-VEN and S-VEN reduced after co-administration of BEZ, while the t_(1/2)of R-ODV and S-ODV increased,especially for the S-ODV, there was great differences(P＜0.05).
So the CYP2D6 has the stereoselective metabolism for the R-VEN and S-VEN but for the R-ODV and S-ODV.
CONCLUSIONS
1.The VEN and ODV enantiomers have the great difference in the metabolism in Chinese healthy volunteers.
2.BEZ can inhibit the metabolism of VEN specifically to the S-ODV after single administration of BEZ.
3.BEZ can inhibt the CYP2D6,so co-administration of BEZ and VEN could have strong influence on the VEN pharmacokinetics.After being inhibited,the VEN enantiomers C_(max)and AUC increased.The possible reason is that the metabolism of VEN enantiomers by CYP2D6 deduced for the inhibition of CYP2D6.So the C_(max)and AUC of them increased greatly,while the raise of the C_(max)and AUC of ODV enantiomers is due to the inhibition of metabolism of ODV to DDV by by BEZ.
引文
[1]Holliday SM,Benfield P.Venlafaxine:A review of its pharmacology and therapeutic potential in depression[J].Drugs,1995;49(2):280-94
[2]Gex-Fabry M,Rudaz S,Balant-Gorgia AE,et al.Steady-state concentration of venlafaxine enantiomers:model-based analysis of between-patient variability[J].Eur J Clin Pharmacol,2002;58(5):323-31
[3]Eap CB,Bertel-Laubscher R,Zullino D,et al.Marked increase of venlafaxine enantiomer concentrations as a consequence of metabolic interactions:a case report[J].Pharmacopsychiatry,2000;33(3):112-5
[4]Fukuda T,Nishida Y,Zhou Q,et al.The impact of the CYP2D6 and CYP2C19genotypes on venlafaxine pharmacokinetics in a Japanese population[J].Eur J Clin Pharmacol,2000;56(2):175-80
[5]Klamerus KJ,Parker VD,Rudolph RL,et al.Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics[J].Pharmacotherapy,1996;16(5):915-23
[6]王娜,刘会臣,候艳宁.细胞色素P4502D6与药物代谢[J].中国临床药理学杂志,2001;17(4):308-12
[7]季闽春,王永铭.细胞色素P4502D6多态性研究[J].中国临床药理学杂志,2000;16(3):225-7
[8]Furman KD,Grimm DR,Mueller T.et al Impact of CYP2D6 intermediate metabolizer alleles on single-dose desipramine pharmacokinetics[J]Pharmacogenetics 2004,14(5):279-84
[9]Kaqiomoto M,Heim M,Kaqimoto K.et al.Multriple mutations of the human cytochrome P450 Ⅱ D6 gene(CYP2D6)in poor metabolizers of debrisoquine.Study of the functional significance of individual mutations by expression of chimeric gene.[J]J Bio Chem.1990.265(28):17209-14
[10]Zhou HH,Wood AJJ,Stereoselective disposition ofcarvedilol is determined by CYP2D6.[J]Clin Pharmacol Ther 1995.57:518-24
[11]Cai W M,Chen B,Cai M H et al.CYP2D6 phentype determines pharmacokinetic variability of propafenone enantiomers in 16 Han Chinese subjects[J]Acta Pharmacol Sin 1999;20(8):720-24
[12]Yu A M,Byron M K,Allan E.R et al.Expression,purification,bioachemical characterization and comparative function of human cytochrome P4502D6.1,2D6.2,2D6.10,and 2D6.17 allelic isoforms.[J]J Pharma Exper Ther,2002;303:1291-1300.
[13]K.helen ekborgott,Youbang Liu,D.W.Armstrong.Highly enantioselective HPLC separations using the covalently bonded macrocyclic antibiotic,Ristocetin A,chiral stationary phase.[J]Chirality 1998,10:434-483
[14]YE,Xiao-Xia,YU Xiong,Glycopeptide antibiotics-bonded chiral stationary phase for chiral separation in HPLC[J].Chin J Pharm,2002,33(4):194-198
[15]Susan F.Murphy-Poulton,Frances Boyle,Xiao Qing Gb,et al.Thalidomide enantiomers:Determination in biological samples by HPLC and vancomycin-CSP.[J]J of chromatograph B,2006,831:48
[16]Wonku Kang,Dong-Jun Lee,Kwang-Hyeon Liu et al.Analysis of benidipine enantiomers in human plasma by liquid chromatography-mass spectrometry using a macrocyclic antibiotic(Vancomycin)chiral stationary phase column.[J]J chromatograph B,2005,814:75
[17]Kosel M,Eap CB,Amey M,Analysis of the enantiomers of citalopram and its demethylated metabolites using chiral liquid chromatography.[J]J chromatogr B Biomed Sci Appl.1998.719:234
[18]Wang P.C,Howell S.R,Scatin J et al.The disposition of venlafaxine enantiomers in dogs,rats,and humans receiving venlafaxine.[J]Chirality 1992.4:84
[19]Fanual S.Ruidaz S,Veuthey J.L et al Use of vancomycin silica stationary phase in packed capillary electrochromatography.Ⅱ.Enantiomer separation of venlafaxine and O-desmethylvenlafaxine in human plasma.[J]J Chromatogr A 2001,919:195
[20]Rudaz S,Stella C,Balant-Gorqia A.E.,Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in clinical samples by capillary electrophoresis using charged cyclodextrins.[J]J Pharm.Bio Anal 2000,23:107
[21]Liu Wen,Wang Feng,Li H D,Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in human plasma by HPLC-ESI/MS using a vancomycin chiral column.[J]J Chromatogr B Analyst Technol Biomed Life Sci.2006 Nov 29
[22]Troy SM,Rudolph R,Mayersohn M,et al.The influence of cimetidine on the disposition kinetics of the antidepressant venlafaxine[J].J Clin Pharmacol,1998;38(5):467-74
[23]Amchin J,Zarycranski W,Taylor KP,et al.Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine[J].J Clin Pharmacol,1999;39(3):252-9
[24]Troy SM,Parker VP,Hicks DR,et al.Pharmacokinetics and effect of food on the bioavailability of orally administered venlafaxine[J].J Clin Pharmacol,1997;37(10):954-61
[25]Ciusani E,Zullino DF,Eap CB,et al.Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine:pharmacokinetic and clinical aspects[J].J Psychopharmacol.2004;18(4):559-66
[26]Jin Y,Desta Z,Steams V,et al.CYP2D6 genotype,antidepressant use,and tamoxifen metabolism during adjuvant breast cancer treatment[J].J Natl Cancer Inst.2005;97(1):30-9
1 YOU Qi-Dong(尤启东),Ling Guo-qiang(林国强),Chiral Drug-research and application(手性药物-研究与应用).Chemical lndustry Press(化学工业出版社),Beijing(北京),2004.1
2 K.helen ekborgott,Youbang Liu,D.W.Armstrong.Highly enantioselective HPLC separations using the covalently bonded macrocyclic antibiotic,Ristocetin A,chiral stationary phase.Chirality 1998,10:434-483
3 YE,Xiao-Xia(叶晓霞),YU Xiong(俞雄)Glycopeptide antibiotics-bonded chiral stationary phase for chiral separation in HPLC(一种新的手性柱:糖肽抗生素手性柱).Chin J Pharm(中国医药工业杂志),2002,33(4):194-198
4 Timothy J.Ward,Alton B.Farris Ⅲ,Chiral separations using the macrocyclic antibiotics:a review.J of chromatograph A,2001,906:73-89
5 Z.Bosakova,E.Cunnova,E.Tesarov,Comparison of vancomycin-based stationary phases with different chiral selector coverage for enantioselective separation of selected drugs in high-performance liquid chromatography.J of chromatograph A,2005,1088:94-103
6 Wonku Kang,Dong-Jun Lee,Kwang-Hyeon Liu et al.Analysis of benidipine enantiomers in human plasma by liquid chromatography-mass spectrometry using a macrocyclic antibiotic(Vancomycin)chiral stationary phase column.J of chromatograph B,2005,814:75-81
7 L.Ramos,R.Bakhtiar,T.Majumdar et al.Liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry enantiomeric separation of dl-thero-methylphenidate,(Ritalin)using a macrocyclic antibiotic as the chiral selector.Rap commun in mass spectro 1999,13:2054-2062
8 Slama I,E.Jourdan,A.Villet,et al.Temperature and solute molecular size effects on the retention and enantioselectivity of a series of D,L-Dansyl Amino Acids on a vancomycin-based chiral stationary phase.Chromatographia 2003,58:399-404
9 Zuzana Bosakova,Iveta Klouckova,Eva Tesarova,Study of the stability of promethazine enantiomers by liquid chromatography using a vancomycin-bonded chiral stationary phase.J of chromatograph B,2002,707:63-69
10 Mohamed M.Hefnawy,Hassan Y.Aboul-Enein,A validated LC method for the determination of vesamicol enantiomers in human plasma using vancomycin chiral stationary phase and solid phase extraction.J of Pharmace and Biomed Anal2004,35: 535-543
11 Susan F.Murphy-Poulton,Frances Boyle,Xiao Qing Gb, et al. Thalidomide enantiomers: Determination in biological samples by HPLC and vancomycin-CSP.J of chromatograph 5,2006,831:48-56
12 Gianpiero Boatto,Maria Nieddu,Maria Virginia Faedda et al. Enantiomeric separation by HPLC of 1,4-dihydropyfidines with vancomycin as chiral selector.Chirality 2003,15:494-497
13 Pavel Jandera ,Veronika Backovska, Attila Felinger .Analysis of the band profiles of the enantiomers of phenylglycine in liquid chromatography on bonded teicoplanin columns using the stochastic theory of chromatography. J of chromatograph A,2001,919:67-77
14 Jana Lokajova,Eva Tesarova,Daniel W.Armstrong, Comparative study of three teicoplanin-based chiral stationary phases using the linear free energy relationship model. J of chromatograph A,2005,1088:57-66
15 Alain Berthod1,Youbang Liu,Christina Bagwill, et al. Facile liquid chromatographic enantioresolution of native amino acids and peptides using a teicoplanin chiral stationary phase J of chromatograph A,1996,731:123-137
16 Alberto Cavazzini,Giorgio Nadalini,Francesco Dondi et a. l Study of mechanisms of chiral discrimination of amino acids and their derivatives on a teicoplanin-based chiral stationary phase. J of chromatograph 42004,1031:143-158
17 Antal Peter, Anita Arki, Dirk Tourwe, Comparison of the separation efficiencies of Chirobiotic T and TAG columns in the separation of unusual amino acids. J of chromatograph A,2004,1031:159-170
18 Antal Peter,Roland Torok,D. W.Armstrong. Direct high-performance liquid chromatographic separation of unusual secondary amino acids and a comparison of the performances of Chirobiotic T and TAG columns. J of chromatograph 42004,1057:229-235
19 T.J.Ward,Alton B.F.,K.Woodling. Synergistic chiral separations using the glycopeptides ristocetin A and Vancomycin. J Biochem.Biophys.Methods.2001,48:163-174
20 Antal Peter,Gabriella Torok,D.W.Armstrong. High-performance liquid chromatographic separation of enantiomers of synthetic amino acids on a ristocetin A chiral stationary phase. J of chromatograph A,2000,904:1-15
21 Antal Petera,Erika Vekes,D. W.Armstrong, Effects of temperature on retention of chiral compounds on a ristocetin A chiral stationary phase. J of chromatograph 42002,958:89-107
22 Alain Berthod,T.L.Xiao,Ying Liu et al Separation of chiral sulfoxides by liquid chromatography using macrocyclic glycopeptide chiral stationary phases. J of chromatograph 42002,95:53-69
23 Antal Peter,Gabriella Torok,Daniel W.Armstrong, et al. Effect of temperature on retention of enantiomers of P-methyl amino acids on a teicoplanin chiral stationary phase. J of chromatograph 5,1998,882:177-190
24 R.Berkecz, R.Torok, I.Ilisz, et al. LC enantioseparation of β-lactam,and β-amino acid stereoisomers and a comparison of macrocyclic and β-cyclodextrin-based columns.Chromatographia 2006,1,28
25 G.S.Ding,X.J.Huang,Y.Liu et al.Chiral separation of racemates of drugs and amino acid derivatives by high-performance liquid chromatography on a norvancomycin-bonded chiral stationary phase.Chromatographia 2004,59:443-449
[2]Gex-Fabry M,Rudaz S,Balant-Gorgia AE,et al.Steady-state concentration of venlafaxine enantiomers:model-based analysis of between-patient variability[J].Eur J Clin Pharmacol,2002;58(5):323-31
[3]Eap CB,Bertel-Laubscher R,Zullino D,et al.Marked increase of venlafaxine enantiomer concentrations as a consequence of metabolic interactions:a case report[J].Pharmacopsychiatry,2000;33(3):112-5
[4]Fukuda T,Nishida Y,Zhou Q,et al.The impact of the CYP2D6 and CYP2C19genotypes on venlafaxine pharmacokinetics in a Japanese population[J].Eur J Clin Pharmacol,2000;56(2):175-80
[5]Klamerus KJ,Parker VD,Rudolph RL,et al.Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics[J].Pharmacotherapy,1996;16(5):915-23
[6]王娜,刘会臣,候艳宁.细胞色素P4502D6与药物代谢[J].中国临床药理学杂志,2001;17(4):308-12
[7]季闽春,王永铭.细胞色素P4502D6多态性研究[J].中国临床药理学杂志,2000;16(3):225-7
[8]Furman KD,Grimm DR,Mueller T.et al Impact of CYP2D6 intermediate metabolizer alleles on single-dose desipramine pharmacokinetics[J]Pharmacogenetics 2004,14(5):279-84
[9]Kaqiomoto M,Heim M,Kaqimoto K.et al.Multriple mutations of the human cytochrome P450 Ⅱ D6 gene(CYP2D6)in poor metabolizers of debrisoquine.Study of the functional significance of individual mutations by expression of chimeric gene.[J]J Bio Chem.1990.265(28):17209-14
[10]Zhou HH,Wood AJJ,Stereoselective disposition ofcarvedilol is determined by CYP2D6.[J]Clin Pharmacol Ther 1995.57:518-24
[11]Cai W M,Chen B,Cai M H et al.CYP2D6 phentype determines pharmacokinetic variability of propafenone enantiomers in 16 Han Chinese subjects[J]Acta Pharmacol Sin 1999;20(8):720-24
[12]Yu A M,Byron M K,Allan E.R et al.Expression,purification,bioachemical characterization and comparative function of human cytochrome P4502D6.1,2D6.2,2D6.10,and 2D6.17 allelic isoforms.[J]J Pharma Exper Ther,2002;303:1291-1300.
[13]K.helen ekborgott,Youbang Liu,D.W.Armstrong.Highly enantioselective HPLC separations using the covalently bonded macrocyclic antibiotic,Ristocetin A,chiral stationary phase.[J]Chirality 1998,10:434-483
[14]YE,Xiao-Xia,YU Xiong,Glycopeptide antibiotics-bonded chiral stationary phase for chiral separation in HPLC[J].Chin J Pharm,2002,33(4):194-198
[15]Susan F.Murphy-Poulton,Frances Boyle,Xiao Qing Gb,et al.Thalidomide enantiomers:Determination in biological samples by HPLC and vancomycin-CSP.[J]J of chromatograph B,2006,831:48
[16]Wonku Kang,Dong-Jun Lee,Kwang-Hyeon Liu et al.Analysis of benidipine enantiomers in human plasma by liquid chromatography-mass spectrometry using a macrocyclic antibiotic(Vancomycin)chiral stationary phase column.[J]J chromatograph B,2005,814:75
[17]Kosel M,Eap CB,Amey M,Analysis of the enantiomers of citalopram and its demethylated metabolites using chiral liquid chromatography.[J]J chromatogr B Biomed Sci Appl.1998.719:234
[18]Wang P.C,Howell S.R,Scatin J et al.The disposition of venlafaxine enantiomers in dogs,rats,and humans receiving venlafaxine.[J]Chirality 1992.4:84
[19]Fanual S.Ruidaz S,Veuthey J.L et al Use of vancomycin silica stationary phase in packed capillary electrochromatography.Ⅱ.Enantiomer separation of venlafaxine and O-desmethylvenlafaxine in human plasma.[J]J Chromatogr A 2001,919:195
[20]Rudaz S,Stella C,Balant-Gorqia A.E.,Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in clinical samples by capillary electrophoresis using charged cyclodextrins.[J]J Pharm.Bio Anal 2000,23:107
[21]Liu Wen,Wang Feng,Li H D,Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in human plasma by HPLC-ESI/MS using a vancomycin chiral column.[J]J Chromatogr B Analyst Technol Biomed Life Sci.2006 Nov 29
[22]Troy SM,Rudolph R,Mayersohn M,et al.The influence of cimetidine on the disposition kinetics of the antidepressant venlafaxine[J].J Clin Pharmacol,1998;38(5):467-74
[23]Amchin J,Zarycranski W,Taylor KP,et al.Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine[J].J Clin Pharmacol,1999;39(3):252-9
[24]Troy SM,Parker VP,Hicks DR,et al.Pharmacokinetics and effect of food on the bioavailability of orally administered venlafaxine[J].J Clin Pharmacol,1997;37(10):954-61
[25]Ciusani E,Zullino DF,Eap CB,et al.Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine:pharmacokinetic and clinical aspects[J].J Psychopharmacol.2004;18(4):559-66
[26]Jin Y,Desta Z,Steams V,et al.CYP2D6 genotype,antidepressant use,and tamoxifen metabolism during adjuvant breast cancer treatment[J].J Natl Cancer Inst.2005;97(1):30-9
1 YOU Qi-Dong(尤启东),Ling Guo-qiang(林国强),Chiral Drug-research and application(手性药物-研究与应用).Chemical lndustry Press(化学工业出版社),Beijing(北京),2004.1
2 K.helen ekborgott,Youbang Liu,D.W.Armstrong.Highly enantioselective HPLC separations using the covalently bonded macrocyclic antibiotic,Ristocetin A,chiral stationary phase.Chirality 1998,10:434-483
3 YE,Xiao-Xia(叶晓霞),YU Xiong(俞雄)Glycopeptide antibiotics-bonded chiral stationary phase for chiral separation in HPLC(一种新的手性柱:糖肽抗生素手性柱).Chin J Pharm(中国医药工业杂志),2002,33(4):194-198
4 Timothy J.Ward,Alton B.Farris Ⅲ,Chiral separations using the macrocyclic antibiotics:a review.J of chromatograph A,2001,906:73-89
5 Z.Bosakova,E.Cunnova,E.Tesarov,Comparison of vancomycin-based stationary phases with different chiral selector coverage for enantioselective separation of selected drugs in high-performance liquid chromatography.J of chromatograph A,2005,1088:94-103
6 Wonku Kang,Dong-Jun Lee,Kwang-Hyeon Liu et al.Analysis of benidipine enantiomers in human plasma by liquid chromatography-mass spectrometry using a macrocyclic antibiotic(Vancomycin)chiral stationary phase column.J of chromatograph B,2005,814:75-81
7 L.Ramos,R.Bakhtiar,T.Majumdar et al.Liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry enantiomeric separation of dl-thero-methylphenidate,(Ritalin)using a macrocyclic antibiotic as the chiral selector.Rap commun in mass spectro 1999,13:2054-2062
8 Slama I,E.Jourdan,A.Villet,et al.Temperature and solute molecular size effects on the retention and enantioselectivity of a series of D,L-Dansyl Amino Acids on a vancomycin-based chiral stationary phase.Chromatographia 2003,58:399-404
9 Zuzana Bosakova,Iveta Klouckova,Eva Tesarova,Study of the stability of promethazine enantiomers by liquid chromatography using a vancomycin-bonded chiral stationary phase.J of chromatograph B,2002,707:63-69
10 Mohamed M.Hefnawy,Hassan Y.Aboul-Enein,A validated LC method for the determination of vesamicol enantiomers in human plasma using vancomycin chiral stationary phase and solid phase extraction.J of Pharmace and Biomed Anal2004,35: 535-543
11 Susan F.Murphy-Poulton,Frances Boyle,Xiao Qing Gb, et al. Thalidomide enantiomers: Determination in biological samples by HPLC and vancomycin-CSP.J of chromatograph 5,2006,831:48-56
12 Gianpiero Boatto,Maria Nieddu,Maria Virginia Faedda et al. Enantiomeric separation by HPLC of 1,4-dihydropyfidines with vancomycin as chiral selector.Chirality 2003,15:494-497
13 Pavel Jandera ,Veronika Backovska, Attila Felinger .Analysis of the band profiles of the enantiomers of phenylglycine in liquid chromatography on bonded teicoplanin columns using the stochastic theory of chromatography. J of chromatograph A,2001,919:67-77
14 Jana Lokajova,Eva Tesarova,Daniel W.Armstrong, Comparative study of three teicoplanin-based chiral stationary phases using the linear free energy relationship model. J of chromatograph A,2005,1088:57-66
15 Alain Berthod1,Youbang Liu,Christina Bagwill, et al. Facile liquid chromatographic enantioresolution of native amino acids and peptides using a teicoplanin chiral stationary phase J of chromatograph A,1996,731:123-137
16 Alberto Cavazzini,Giorgio Nadalini,Francesco Dondi et a. l Study of mechanisms of chiral discrimination of amino acids and their derivatives on a teicoplanin-based chiral stationary phase. J of chromatograph 42004,1031:143-158
17 Antal Peter, Anita Arki, Dirk Tourwe, Comparison of the separation efficiencies of Chirobiotic T and TAG columns in the separation of unusual amino acids. J of chromatograph A,2004,1031:159-170
18 Antal Peter,Roland Torok,D. W.Armstrong. Direct high-performance liquid chromatographic separation of unusual secondary amino acids and a comparison of the performances of Chirobiotic T and TAG columns. J of chromatograph 42004,1057:229-235
19 T.J.Ward,Alton B.F.,K.Woodling. Synergistic chiral separations using the glycopeptides ristocetin A and Vancomycin. J Biochem.Biophys.Methods.2001,48:163-174
20 Antal Peter,Gabriella Torok,D.W.Armstrong. High-performance liquid chromatographic separation of enantiomers of synthetic amino acids on a ristocetin A chiral stationary phase. J of chromatograph A,2000,904:1-15
21 Antal Petera,Erika Vekes,D. W.Armstrong, Effects of temperature on retention of chiral compounds on a ristocetin A chiral stationary phase. J of chromatograph 42002,958:89-107
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