人体内反式曲马朵及其活性代谢产物反式氧去甲基曲马朵对映体的药物动力学(英文)

目的:研究反式曲马朵(trans-T)及其活性代谢产物反式氧去甲基曲马朵(M1)的人体药代动力学立体选择性。方法:12名健康男性受试者口服多剂量盐酸trans-T缓释片后,采用高效毛细管电泳(HPCE)法测定血清中trans-T及M1对映体的浓度。结果:血清中trans-T对映体浓度达稳态后,不同时间血清中( )-trans-T的浓度均高于(-)-trans-T的浓度,两对映体除T_(max)以外的药代动力学参数的差异均有显著性。在大多数受试者体内和大多数取血时间点,(-)-M1的浓度高于( )-M1的浓度;在不同受试者体内,血清中M1对映体浓度的比值差别较大,两对映体的C_(max)和C_(min)差异有显著性。结论:trans-T和M1具有药代动力学立体选择性。人体对( )-trans-T比对(-)-trans-T吸收完全,消除慢;在不同受试者体内,M1的药代动力学立体选择性是不同的。     

在大鼠肝微粒体中反式曲马朵代谢及反式氧去甲基曲马朵生成的立体选择性(英文)

目的:研究反式曲马朵[(±)一trans-T]代谢及反式氧去甲基曲马朵(M1)生成的立体选择性,方法:(±)-trans-T及其对映体分别与大鼠肝微粒体孵育,高效毛细管电泳法测定孵育液中(±)-trans-T及M1对映体的浓度。结果:以(±)-trans-T单一对映体为底物孵育时,(+)-trans-T的代谢速率较低,(+)-M1生成有较低的V_(max)和CL_(int).以(±)-trans-T消旋体为底物孵育时,(±)-trans-T对映体的代谢速率及(±)-M1对映体的生成速率不同程度地减慢。右美沙芬、普罗帕酮和氟西汀既能抑制(±)-trans-T的代谢,又能抑制M1的生成;普罗帕酮和氟西汀能增强(±)-trans-T代谢及M1生成的立体选择性,右美沙芬仅使M1生成的立体选择性增强。结论:在大鼠肝微粒体中,(±)-trans-T代谢及M1生成有立体选择;(±)-trans-T对映体间存在相互作用。右美沙芬、普罗帕酮及氟西汀对它们的立体选择性产生不同的影响。     

盐酸反式曲马朵口服制剂中盐酸曲马朵立体异构体的分离与测定

目的 :建立盐酸反式曲马朵口服制剂中盐酸曲马朵 4种立体异构体的分离测定方法。方法 :采用高效毛细管电泳法 ,未涂层毛细管 75 μm× 37cm (有效长度 30cm) ;分离介质为 40mmol·L-1Tris缓冲液 (pH 2 5 ) ,内含 0 8mmol·L-1磺丁基 - β-环糊精 ;分离电压 15kV ,柱温 2 5℃ ,检测波长 2 14nm ;进样电压 10kV ,2 0s ,入口为阳极。 结果 :以 (- ) -氧去甲基曲马朵为内标 ,反式曲马朵、顺式曲马朵的对映体达到基线分离 ,( ) -盐酸反式曲马朵、 (- ) -反式曲马朵的线性浓度范围为 0 5～ 1 5 μg·mL-1;4种制剂中 ( ) -盐酸反式曲马朵和 (- ) -盐酸曲马朵平均回收率 96 87%～10 2 4%和 96 2 8%～ 10 1 3 % ,RSD <5 % ,n =5 ;盐酸曲马朵 4种立体异构体的最低检测浓度为 5ng·mL-1;4种盐酸反式曲马朵口服制剂中盐酸顺式曲马朵各对映体含量不超过 0 12 % ,盐酸反式曲马朵各对映体的含量为标示量的 45 5 8%～5 0 93 %。结论 :本方法可用于盐酸反式曲马朵口服制剂中盐酸顺式曲马朵对映体的限量检查和盐酸反式曲马朵对映体的含量测定     

反式曲马朵及其活性代谢产物反式氧去甲基曲马朵肾脏清除的立体选择性

目的:研究反式曲马朵及其活性代谢物反式氧去甲基曲马朵肾脏清除的立体选择性.方法:取雄性SD大鼠的右肾,分别以含反式曲马朵(300μg/L)或反式氧去甲基曲马朵(50μg/L)的灌流液(10mL)进行灌流;利用高效毛细管电泳法测定灌流后灌流液、尿液中反式曲马朵及反式氧去甲基曲马朵对映体的浓度,并计算对映体浓度比值.结果:以反式曲马朵进行离体肾灌流后,在灌流液中,( )-反式曲马朵的浓度高于(-)-反式曲马朵的浓度,( )-反式氧去甲基曲马朵的浓度低于(-)-反式氧去甲基曲马朵的浓度;在尿液中,( )-反式曲马朵较(-)-反式曲马朵多,( )-反式氧去甲基曲马朵较(-)-反式氧去甲基曲马朵少.以反式氧去甲基曲马朵灌流后,在灌流液中( )-反式氧去甲基曲马朵的浓度低于(-)-反式氧去甲基曲马朵的浓度;在尿液中( )-反式氧去甲基曲马朵较(-)-反式氧去甲基曲马朵高.结论:反式曲马朵及反式氧去甲基曲马朵的肾脏清除具有立体选择性.在肾脏中反式曲马朵的氧去甲基代谢具有立体选择性,以(-)-反式曲马朵优先代谢成(-)-反式氧去甲基曲马朵.反式氧去甲基曲马朵的尿排泄具有立体选择性,以( )-反式氧去甲基曲马朵占优.     

在大鼠肝微粒体中反式曲马朵和反式氧去甲基曲马朵对映体代谢的性别差异

目的研究反式曲马朵(trans T)对映体代谢，反式氧去甲基曲马朵(Ml)对映体生成及其与葡糖醛酸结合的性别差异。方法以trans T或Ml为底物分别与大鼠肝微粒体孵育，高效毛细管电泳法测定孵育液中trans T和Ml对映体。结果与(+)-对映体相比，(-)-trans T优先代谢，(-)-Ml优先生成。在雌性大鼠肝微粒体中(-)-Ml优先与葡糖醛酸结合；Ml两对映体生成及其与葡糖醛酸结合的CL_int比值偏离1的程度较大。在雄性大鼠肝微粒体中(+)-Ml优先与葡糖醛酸结合。结论Trans T代谢，M1生成及其与葡糖醛酸结合均具立体选择性和性别差异；Ml生成及其与葡糖醛酸结合立体选择性的程度以雌性大鼠的较高。     

反式曲马朵在大鼠肝微粒体O-去甲基代谢中的立体选择性

目的研究反式曲马朵O-去甲基代谢的立体选择性.方法高效毛细管电泳法测定大鼠肝微粒体孵育液中反式曲马朵和O-去甲基曲马朵对映体的浓度,酶促动力学方法研究O-去甲基曲马朵对映体的生成.结果 (-)-O-去甲基曲马朵生成有较大的Vmax;反式曲马朵两对映体间存在相互作用,使(+)-O-去甲基曲马朵生成的Vmax明显减慢;奎宁及奎尼丁对(+)-O-去甲基曲马朵生成的抑制作用较强.结论反式曲马朵O-去甲基代谢有立体选择性,对映体间的相互作用及酶抑制剂使其立体选择性程度加强.     

反式曲马朵和反式氧去甲基曲马朵在大鼠胆汁中排泄的立体选择性

目的研究反式曲马朵(trans T)及反式氧去甲基曲马朵(M1)在大鼠胆汁中排泄的立体选择性. 方法高效毛细管电泳法测定大鼠iv trans T或 M1后胆汁和血浆中trans T, M1和与葡糖醛酸结合M1(M1c)的对映体.结果大鼠iv trans T后,胆汁中(+)-trans T水平较(-)-trans T高,(+)/(-)-trans T较血浆中(+)/(-)-trans T的比值小.大鼠iv M1后,胆汁中(+)-M1水平较(-)-M1高,(+)-M1c较(-)-M1c低,(+)-M1与葡糖醛酸的结合率较(-)-M1低.结论 Trans T和M1在大鼠胆汁中排泄具立体选择性,(+)-trans T和(-)-M1被优先排泄.     

反式曲马朵和反式氧去甲基曲马朵在大鼠胆汁中排泄的立体选择性反式曲马朵和反式氧去甲基曲马朵在大鼠胆汁中排泄的立体选择性

目的研究反式曲马朵(trans T)及反式氧去甲基曲马朵(M1)在大鼠胆汁中排泄的立体选择性。方法高效毛细管电泳法测定大鼠iv trans T或 M1后胆汁和血浆中trans T, M1和与葡糖醛酸结合M1(M1_c)的对映体。结果大鼠iv trans T后,胆汁中(+)-transT水平较(-)-trans T高,(+)/(-)-trans T较血浆中(+)/(-)-trans T的比值小。大鼠iv M1后,胆汁中(+)-M1水平较(-)-M1高,(+)-M1_c较(-)-M1_c低,(+)-M1与葡糖醛酸的结合率较(-)-M1低。结论trans T和M1在大鼠胆汁中排泄具立体选择性,(+)-trans T和(-)-M1被优先排泄。     

反式曲马朵在大鼠肝微粒体O-去甲基代谢中的立体选择性

目的研究反式曲马朵O-去甲基代谢的立体选择性。方法高效毛细管电泳法测定大鼠肝微粒体孵育液中反式曲马朵和O-去甲基曲马朵对映体的浓度,酶促动力学方法研究O-去甲基曲马朵对映体的生成。结果 (-)-O-去甲基曲马朵生成有较大的V_max;反式曲马朵两对映体间存在相互作用,使(+)-O-去甲基曲马朵生成的V_max明显减慢;奎宁及奎尼丁对(+)-O-去甲基曲马朵生成的抑制作用较强。结论反式曲马朵O-去甲基代谢有立体选择性,对映体间的相互作用及酶抑制剂使其立体选择性程度加强。     

人血清中反式曲马朵与反式氧去甲基曲马朵对映体的测定及其在治疗药物监测中的应用

目的:建立人血清中反式曲马朵((±)-trans T)与氧去甲基曲马朵((±)-M1)对映体的测定方法,研究血清中 (±)-trans T和(±)-M1对映体浓度与临床效果的关系.方法:以磺丁基-β-环糊精为手性选择剂,高效毛细管电泳(HPCE)法测定人血清中(±)-trans T与(±)-M1对映体的浓度;监测20例术后病人静滴盐酸(±)-trans T 400 mg·d-1 或 300 mg·d-1后血清中 (±)-trans T与 (±)-M1对映体浓度,并观察临床镇痛效果及药物不良反应.结果:血清中 (±)-trans T与 (±)-M1对映体分离效果良好,(±)-trans T与 (±)-M1对映体的线性范围分别为20～640 mg.L-1 和10～160mg·L-1,相对回收率在92.30%～107.80%之间,日内RSD小于10%,日间RSD小于15%,最低检测浓度为1.10mg·L-1.400 mg.d-1 组病人血清中(±)-trans T对映体的浓度、药物不良反应的发生率和严重程度明显高于300 mg·d-1 组病人,而400 mg.d-1组和300 mg·d-1组病人血清中(±)-M1对映体浓度及镇痛效果无明显区别.结论:所建立的HPCE方法可用于临床治疗药物监测.血清中(+)-M1的浓度与镇痛效果密切相关,(±)-trans T对映体浓度过高可能是药物不良反应的发生率增高和程度增强的原因之一.     

在大鼠体内反式曲马朵及其活性代谢物反式氧去甲基曲马朵对映体药代动力学的性别差异

AIM: To compare the pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite,trans-O-demethyltramadol (M1), in male and female rats. METHODS: Following a single oral dose of 10 mg/kg trans-T hydrochloride to rats, ( )-trans-T, (-)-trans-T, ( )-M1, and (-)-M 1 in plasma were determined by a high performance capillary electrophoresis method. RESULTS: The females showed higher plasma concentrations of ( )-trans-T, (-)-trans-T, and ( )-M1 than the males. The enantiomers of trans-T were absorbed and eliminated more slowly in the females than in the males. ( )-M1 was eliminated more slowly in the females than in the males.All pharmacokinetic parameters but Tmax of the two enantiomers of trans-T were significantly different in both sex rats. The ( )/(-)-enantiomeric ratios of the pharmacokinetic parameters for trans-T in the males were similar to those in the females. The values of Cmax, AUC0-∞ of the two enantiomers of M1 were significantly different in both sex rats. The ( )/(-)-enantiomeric ratios of Cmax, AUC0-∞ for M 1 were lower than 1 in the males, larger than 1 in the females. CONCLUSIONS: Systemic exposure of ( )-trans-T, (-)-trans-T, and ( )-M 1 was higher in female rats than in male rats. The stereoselectivity in pharmacokinetics of trans-T was similar, and that of M 1 was different in male and female rats.     

反式曲马多及氧去甲基曲马多对映体跨血脑屏障转运

目的　研究反式曲马多(trans T)及其活性代谢物氧去甲基曲马多(M₁)对映体的跨血脑屏障转运。方法大鼠ip盐酸 trans T (16.7mg·kg^-1 或5.0mg·kg^-1) 1 h后取血、脑脊液和大脑皮层,高效毛细管电泳测定血清、脑脊液和大脑皮层中 trans T和M₁ 对映体的浓度。结果　trans T和M₁ 各对映体浓度以大脑皮层中最高,血清中浓度居中,脑脊液中浓度最低。在血清中,(+)-trans T的浓度明显高于(-)-trans T的浓度,M₁ 两对映体的浓度无明显区别;在脑脊液和大脑皮层中,(+)-trans T的浓度明显高于(-)-trans T的浓度,(+)-M₁ 的浓度明显低于(-)-M₁ 的浓度。结论　trans T和M₁ 的跨血脑屏障转运具有立体选择性,脑组织中分别以(+)-对映体和(-)-对映体浓度较高。     

Tissue distribution of mexiletine enantiomers in rats

1. The kinetics of distribution of the enantiomers of mexiletine were studied in various tissues (heart, brain, lungs, liver, kidneys and fat) in male Sprague-Dawley rats after administration of a single i.v. dose (10mg/kg) of racemic mexiletine.

2. The pharmacokinetic parameters calculated from the serum data showed a 32% greater systemic clearance (162ml/min per kg vs 123 ml/rain per kg) and a 22% greater steady-state volume of distribution (9.01/kg vs 7.4 1/kg) for R(-)-mexiletine relative to the S(+)-enantiomer. However, the terminal elimination half-lives of the enantiomers (1.4 and 1.3h for R(-)- and S(+)-mexiletine, respectively) did not exhibit stereoselectivity.

3. Maximum tissue concentrations of the enantiomers were observed at 5?min after dosage in all tissues studied. Stereoselective uptake was evident only in the liver tissue and was 2.4-fold greater for S(+)-mexiletine. High tissue/serum ratios (>20 for both enantiomers) were observed in lungs, brain and kidneys. The cardiac concentrations of R(-)- and S(+)-mexiletine were 8- and 7-fold those of serum, respectively.

4. The results demonstrate that the uptake of mexiletine enantiomers into the target tissue (heart) is not stereoselective. However, the relatively high brain accumulation of the enantiomers may be related to the CNS side-effects commonly associated with mexiletine therapy.     

Tissue distribution of mexiletine enantiomers in rats.

1. The kinetics of distribution of the enantiomers of mexiletine were studied in various tissue (heart, brain, lungs, liver, kidneys and fat) in male Sprague-Dawley rats after administration of a single i.v. dose (10 mg/kg) of racemic mexiletine. 2. The pharmacokinetic parameters calculated from the serum data showed a 32% greater systemic clearance (162 ml/min per kg vs 123 ml/min per kg) and a 22% greater steady-state volume of distribution (9.0 l/kg vs 7.4 l/kg) for R(-)-mexiletine relative to the S(+)-enantiomer. However, the terminal elimination half-lives of the enantiomers (1.4 and 1.3 h for R(-)- and S(+)-mexiletine, respectively) did not exhibit stereoselectivity. 3. Maximum tissue concentrations of the enantiomers were observed at 5 min after dosage in all tissues studied. Stereoselective uptake was evident only in the liver tissue and was 2.4-fold greater for S(+)-mexiletine. High tissue/serum ratios (greater than 20 for both enantiomers) were observed in lungs, brain and kidneys. The cardiac concentrations of R(-)- and S(+)-mexiletine were 8- and 7-fold those of serum, respectively. 4. The results demonstrate that the uptake of mexiletine enantiomers into the target tissue (heart) is not stereoselective. However, the relatively high brain accumulation of the enantiomers may be related to the CNS side-effects commonly associated with mexiletine therapy.     

Electroencephalographic effects of thiopentone and its enantiomers in the rat: correlation with drug tissue distribution

1. To better understand the pharmacology of the thiopentone enantiomers, we studied their quantitative electroencephalographic effects and their distribution into vital tissues. 2. Adult Wistar rats were infused with rac-, R- or S-thiopentone at 4 mg kg(-1)min(-1) until death ensued. The EEG signal was acquired continuously; serial arterial plasma and terminal tissue thiopentone concentrations were measured enantiospecifically. Relevant drug tissue : plasma distribution coefficients and plasma concentration-EEG effect relationships were determined. 3. Doses (mg kg(-1)) (mean+/-s.e.mean) for anaesthesia (toe pinch) and lethality (respiratory failure), respectively, decreased in the order R-thiopentone (55.8+/-2.4 and 176.2+/-11.2)> rac-thiopentone (39.3+/-2.1 and 97.5+/-3.9)> S-thiopentone (35.6+/-1.9 and 74.2+/-5.2); plasma drug concentrations (microg ml(-1)) decreased in the order R-thiopentone (66.3+/-4.5 and 89.8+/-5.2)> rac-thiopentone (56.7+/-2.0 and 77. 8+/-2.8)> S-thiopentone (55.0+/-1.9 and 64.1+/-2.8). 4. Initial EEG activation was similar for all thiopentone forms. Plasma drug concentrations for the same extent of EEG deactivation reflected the potency order. 5. After infusion of rac-thiopentone, tissue : plasma distribution coefficients were higher for R- than for S-thiopentone in brain and visceral regions, but not in fat or muscle. After infusion of the separate enantiomers, the relative heart : brain distribution ratio was for S-thiopentone was double that for R-thiopentone. 6. The therapeutic index of R-thiopentone (3.16+/-0. 14) was more advantageous than either rac-thiopentone (2.52+/-0.13) or S-thiopentone (2.10+/-0.14), possibly due to the relatively greater distribution into CNS tissues than heart. The data suggest that R-thiopentone could make a satisfactory single enantiomer substitute for rac-thiopentone.     

The tissue distribution of racemic S-(+)- and R-(R)-(-)-MPPB (1-methyl-5-phenyl-5-propylbarbituric acid) in the rat

Distribution of racemic 1-methyl-5-phenyl-5-propyl-barbituric acid (= racem. MPPB), of the S-(+)- and R-(-)-enantiomer (= (+)- and (-)-MPPB) between serum and several tissues was investigated after i.v. administration of the substances to rats. Anesthesia produced by the racem. MPPB--(+)-MPPB causes convulsions whereas (-)-MPPB is anesthetically active--cannot be explained by a stereoselective difference of the MPPB-concentration measured in serum and brain when giving the enantiomers. Reversely as expected in the brain MPPB-concentration is significantly higher after administration of (+)-MPPB than after that of (-)-MPPB during the appearance of the CNS symptoms.--Significant stereoselectively different MPPB-concentrations, which are time dependent, could also be detected in liver, spleen and fatty tissue; however, in contrast to the brain in these tissues MPPB-concentration is higher after administration of (-)-MPPB than after that of (+)-MPPB. Concentration differences which are measured in liver, spleen and fatty tissue already 1--10 min after i.v. administration of the enantiomers cannot be explained by a stereoselectivity of the metabolism and/or renal elimination. However, a stereoselective metabolism and/or renal elimination of the enantiomers can be responsible for concentration differences which are observed during the late period of 60--180 min after administration: in serum, brain, liver and fatty tissue MPPB-concentration is lower if (4)-MPPB is administered. For that reason it can be supposed that (+)-MPPB is faster eliminated than (-)-MPPB.     

Pharmacokinetics of propafenone enantiomers in rats

Pharmacokinetics of propafenone (PPF) enantiomers were investigated in adult male Sprague-Dawley rats after iv, po, and ip administration of a single 10 mg/kg dose of the racemate. After all routes of administration, the AUC for the (-)-enantiomer was significantly higher than that of its antipode: the mean +/- SD values of (-):(+) AUC ratio were 1.99 +/- 0.228, 2.52 +/- 0.525, and 3.54 +/- 1.12 for the iv, ip, and po data, respectively. The respective absolute bioavailabilities of the (-)- and (+)-enantiomers were 0.422 and 0.254 after po administration and 0.493 and 0.402 after ip administration, indicating stereoselectivity in the first-pass metabolism of the drug. Only negligible amounts of the enantiomers were excreted unchanged into the urine of rats, suggesting that elimination of PPF in rats, as in humans, is almost entirely dependent on its metabolism. Compared with the iv and ip data, serum concentrations of the enantiomers after po administration remained above the assay sensitivity for a longer period of time. This was due to the presence of multiple peaks in the serum concentration-time courses of the enantiomers after po administration. In an exploratory experiment, it was shown that co-administration of quinidine sulfate drastically increases serum concentrations of both PPF enantiomers. The results of our study indicate that, in rats, pharmacokinetics of PPF are stereoselective and that the route of administration affects the degree of this stereoselectivity.     

Brain pharmacokinetics and tissue distribution of tetrahydropalmatine enantiomers in rats after oral administration of the racemate

Tetrahydropalmatine (THP), a racemic mixture, is a biologically active ingredient isolated from a traditional Chinese herb Rhizoma Corydalis (yanhusuo). The main objective of this study was to determine the brain pharmacokinetics and tissue distribution of THP enantiomers in rats after oral administration of racemic THP (rac-THP). Rats (5 animals/group/per time) were given a single oral dose of rac-THP and killed after different post-treatment times. The concentrations of THP enantiomers in plasma, cortex, cerebellum, diencephalon, brain stem, striatum and hippocampus were measured using a validated chiral high performance liquid chromatographic (HPLC) method coupled with an achiral column. The pharmacokinetic profiles of the two enantiomers in six brain regions were significantly different. The peak concentrations (Cmax) and AUC(0-infinity) values of the (-)-enantiomer were significantly greater than the corresponding values for the (+)-enantiomer while the striatum contained the highest peak concentrations compared with the plasma and other brain regions. The tissue distribution studies also revealed significant differences between the two enantiomers in all tissues except the lung. The highest concentrations of both enantiomers were found in the liver. The (-)/(+)-THP ratios in six brain regions and other tissues were consistent with that observed in plasma indicating that the stereoselective disposition of THP in rat brain and other tissues reflects the situation in plasma.     

甲氧氯普胺对吗啡依赖性小鼠戒断症状和脑区cGMP含量的影响

目的 :观察甲氧氯普胺脑室给药对吗啡依赖小鼠戒断症状的影响以及腹腔给药对小鼠不同脑区cGMP含量的影响。方法 :皮下注射 (sc)盐酸吗啡建立吗啡依赖小鼠实验模型 ,在纳洛酮催促戒断前 30min侧脑室微量注射甲氧氯普胺 ,观察其急性给药对吗啡依赖性戒断症状的影响 ;用放射性免疫法观察腹腔注射 (ip)甲氧氯普胺对吗啡依赖小鼠小脑、大脑皮层、海马及丘脑四个脑区cGMP含量的影响。结果 :甲氧氯普胺 (1 0mg·kg- 1 )可有效抑制纳洛酮催促的吗啡依赖小鼠的跳跃反应 (P <0 0 1) ;吗啡依赖小鼠四个脑区中cGMP含量均低于正常鼠 (P <0 0 1) ,甲氧氯普胺急性给药 (2 0mg·kg- 1 ,ip)可使吗啡依赖小鼠cGMP接近正常水平。结论 :中枢神经系统是甲氧氯普胺抑制吗啡依赖小鼠戒断跳跃反应的主要作用部位 ;脑区cGMP水平的恢复作用可能是其抑制吗啡戒断的主要机制之一