地尔硫对地高辛作用的研究

本文采用荧光偏振免疫法研究了9例长期使用地高辛患者的血药浓度,结果发现,在加服地尔硫1wk后,地高辛的稳态血药浓度升高(P<0.05),肝肾功能不全患者的升高程度更大;患者的血压和心率均下降(P<0.01);有二例不良反应。     

Pharmacokinetic interaction between fluvastatin and diltiazem in rats

The present study aimed to investigate the effect of fluvastatin on the pharmacokinetics of diltiazem in rats. Pharmacokinetic parameters of diltiazem were determined in rats following an oral administration of diltiazem (15 mg/kg) in the presence and absence of fluvastatin (0.6 and 2.0 mg/kg). Compared with the control given diltiazem alone, the C(max) and AUC of diltiazem increased by 30-70% in rats with the concurrent use of fluvastatin, while there was no significant change in T(max) and the plasma half-life (T(1/2)) of diltiazem. Consequently, absolute and relative bioavailability values of diltiazem in the presence of fluvastatin were significantly higher (p<0.05) than those from the control group, implying that fluvastatin could reduce the presystemic extraction of diltiazem. In conclusion, the concurrent use of fluvastatin significantly enhanced the oral exposure of diltiazem in rats.     

Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein

AIMS: Fexofenadine is a substrate of several drug transporters including P-glycoprotein. Our objective was to evaluate the possible effects of two P-glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P-glycoprotein activity in vivo, and compare the inhibitory effect between the two in healthy volunteers. METHODS: In a randomized three-phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing. RESULTS: Itraconazole pretreatment significantly increased mean (+/-SD) peak plasma concentration (Cmax) of fexofenadine from 699 (+/-366) ng ml-1 to 1346 (+/-561) ng ml-1 (95% CI of differences 253, 1040; P<0.005) and the area under the plasma concentration-time curve [AUC0,infinity] from 4133 (+/-1776) ng ml-1 h to 11287 (+/-4552) ng ml-1 h (95% CI 3731, 10575; P<0.0001). Elimination half-life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affect Cmax (704+/-316 ng ml-1, 95% CI -145, 155), AUC0, infinity (4433+/-1565 ng ml-1 h, 95% CI -1353, 754), or other pharmacokinetic parameters of fexofenadine. CONCLUSIONS: Although some drug transporters other than P-glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first-pass effect by inhibiting the P-glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P-glycoprotein activity in vivo.     

卡马西平与地尔硫卓的相互作用

本文采用高效液相色谱法测定卡马西平与地尔硫的血药浓度，在九只家兔中按正交拉丁方设计比较单用卡马西平、地尔硫和合用两药时体内的双向药物浓度变化和药物动力学参数。结果表明，两药合用时他们的半衰期或消除速度常数比单用有显著变化，建议避免两药合用。在实验中发现卡马西平有双峰现象，估计与肠─肝循环有关。     

Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism

1   The interaction between triazolam and two antifungal agents, fluconazole and terbinafine, was investigated in a double-blind, randomized crossover study of three phases.
2   Twelve healthy young volunteers received 100  mg fluconazole, 250  mg terbinafine or placebo orally once a day for 4 days. On day 4 they took a single 0.25  mg dose of triazolam. Plasma samples were collected and pharmacodynamic effects were measured up to 17  h after the intake of triazolam.
3   Fluconazole increased the area under the triazolam concentration time-curve more than twofold ( P <0.001) and prolonged the elimination half-life of triazolam nearly twofold ( P <0.001). The peak concentration of triazolam was also increased significantly ( P <0.05) by fluconazole.
4   During the fluconazole phase pharmacodynamic effects of triazolam (e.g. digit symbol substitution test, body sway and drowsiness) were enhanced significantly (P<0.05) when compared with the placebo phase.
5   Terbinafine did not change significantly the pharmacokinetics or pharmacodynamics of triazolam.
6   Care should be taken when triazolam is prescribed to patients using fluconazole. Although the interaction is not as strong as that of triazolam with ketoconazole or itraconazole, it is clinically significant. Triazolam and probably other drugs metabolized by CYP3A4 can be used in normal doses with terbinafine.     

Effect of concomitant colestipol hydrochloride administration on the bioavailability of diltiazem from immediate- and sustained-release formulations

Effects of concomitant colestipol administration on plasma concentrations of diltiazem and desacetyldiltiazem from immediate-release (IR) and sustained-release (SR) formulations were assessed in two studies. In the first study, 12 subjects received 120-mg diltiazem hydrochloride (diltiazem) SR capsules or 120-mg diltiazem IR tablets administered alone and in combination with colestipol hydrochloride (colestipol). Following concomitant administration of SR diltiazem with colestipol, AUC(0-infinity ) and C(max), respectively, were 22 and 36% less, and were 27 and 33% lower for IR diltiazem. In the second study, subjects received 120-mg diltiazem SR capsules at staggered times, without colestipol, 1 h prior to or 4 h following multiple doses of colestipol. A 17% decrease in AUC(0-infinity ) was observed when diltiazem was taken 1 h before colestipol was given, and a 22% decrease when diltiazem was taken 4 h after colestipol, relative to diltiazem SR alone. C(max) values were similarly decreased. Results from these two studies show that colestipol can cause a significant decrease in diltiazem absorption from both IR and SR dosage forms. Staggering the administration of colestipol and diltiazem SR did not blunt this effect, indicating that concomitant administration of diltiazem and colestipol should be used with caution, and that the efficacy of diltiazem should be monitored to assure adequate dosing.     

地尔硫芯对葛根素药动学的影响

目的:研究地尔硫芯对葛根素血药浓度及药动学参数的影响。方法:应用高效液相色谱法测定与地尔硫芯合用前后葛根素的血药浓度。结果:注射合用后,地尔硫芯在低剂量时(0.5 mg·kg-1)对葛根素的药动学过程无显著性影响(P>0.05),但在高剂量时(2.5 mg·kg-1)有显著性影响(P<0.05)。结论:葛根素与地尔硫芯合用时,在一定浓度范围内,地尔硫芯可抑制葛根素从大鼠体内的消除;二者合并用药时应对葛根素进行临床给药监测。     

Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination

Diltiazem and hydrochlorothiazide are widely used to treat cardiovascular disease, often in combination. The purpose of this investigation was to determine whether a drug–drug pharmacokinetic interaction exists between diltiazem and hydrochlorothiazide. In a randomized, crossover, open study, multiple doses of diltiazem (60 mg four times daily for 21 doses) and hydrochlorothiazide (25 mg twice daily for 11 doses) were administered alone and in combination on three separate occasions to 20 healthy male volunteers. Trough and serial blood samples were collected and plasma was assayed for diltiazem, hydrochlorothiazide, and diltiazem metabolites (desacetyldiltiazem and N-desmethyldiltiazem) using HPLC. Total urine was also collected and quantified for hydrochlorothiazide. Coadministered hydrochlorothiazide did not significantly (p >0.05) alter diltiazem (alone versus combination) steady-state maximum plasma concentration (C; 145 versus 158 ng mL⁻¹, respectively), time to maximum plasma concentration (t_max; 3.0 versus 2.8 h, respectively); area under the plasma concentration–time curve (AUC_ss; 688 versus 771 ng·h mL⁻¹), oral clearance (Cl_oral; 96.2 versus 88.0 L h⁻¹), or elimination half-life (t_1/2; 5.2 versus 5.2 h). Similarly, administration of diltiazem did not significantly (p >0.05) influence hydrochlorothiazide (alone versus combination) C (221 versus 288 ng mL⁻¹), t_max (1.8 versus 2.0 h), AUC_ss (1194 versus 1247 ng·h mL⁻¹), Cl_oral (22.4 versus 21.2 L h⁻¹); t_1/2 (9.8 versus 9.6 h), or renal Cl (15.5 versus 15.2 L h⁻¹). In conclusion, a clinically significant pharmacokinetic interaction between diltiazem and hydrochlorothiazide does not exist. © 1998 John Wiley & Sons, Ltd.     

Effect of diltiazem on the pharmacokinetics of propranolol,metoprolol and atenolol

Summary The pharmacokinetic interaction between diltiazem and three -adrenoceptor blockers propranolol, metoprolol and atenolol was investigated in healthy volunteers given diltiazem 30 mg or placebo t.d.s. for 3 days, followed by a single dose of propranolol 20 mg, metoprolol 40 mg or atenolol 50 mg.The AUCs of propranolol and metoprolol were significantly increased after diltiazem and it significantly prolonged the elimination half-life of metoprolol. In contrast, it did not significantly affect the pharmacokinetics of atenolol. Propranolol significantly decreased the resting pulse rate after diltiazem pretreatment as compared to placebo.The results indicate that diltiazem impaired the clearance of propranolol and metoprolol, which are principally metabolized by an oxidative pathway, and that the kinetic interaction between diltiazem and propranolol may partly be related to the significant reduction in the pulse rate produced by the latter.     

Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration

Deacetyl diltiazem (M₁) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M₁ was administered as a single 5 mg kg⁻¹ dose intravenously (iv) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M₁ and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N-monodesmethyl DTZ (M₂). The t_1/2 and AUC of M₁ and M₂ were 2.1±0.5 and 3.0±1.1 h, and 1300±200 and 240±37 ng h mL⁻¹, respectively. The Cl and Cl_r of M₁ were 60±10 and 0.81±0.63 mL min⁻¹ kg⁻¹, respectively. M₁ significantly decreased blood pressure (SBP and DBP) for up to 1 h post-dose (p <0.05), but had no significant effect on the heart rate (p >0.05). The E_max and EC₅₀ as estimated by the inhibitory sigmoidal E_max model were 20±18% 620±310 ng mL⁻¹, respectively for SBP; 20±8.3% and 420±160 ng mL⁻¹ for DBP. © 1998 John Wiley & Sons, Ltd.     

地尔硫(艹卓)与普罗帕酮在家兔体内的药动学相互作用研究

６只家兔随机交叉实验，分别单用地尔硫、普罗帕酮或合用两药，结果发现合用两药后，普罗帕酮的消除速率常数Ｋｅ和清除率ｃｌｓ／Ｆ较单用时明显减小，消除半衰期ｔ１／２（ｋｅ）平均延长０．７０１小时，第一峰浓度和第二峰浓度分别升高８５．７４％和７５．５５％，ＡＶＣ０－∞增大５６．７５％，且均有显著性意义。地尔硫的ｃｌｓ／Ｆ在合用药后显著降低，Ｖｄ／Ｆ显著减小，地尔硫及其活性代谢物去乙酰地尔硫的峰浓度则分别增大１２９．８３％和１１９．１３％。表明两药合用后普罗帕酮的肝脏代谢受到抑制，同时普罗帕酮也影响了地尔硫的体内吸收或处置过程。提示临床两药合用时应同时监测患者血浓，避免不良反应的发生。     

高效液相色谱法测定人体地尔硫及其主要代谢物的药物动力学

用高效液相色谱法（ＨＰＬＣ）测定人血清中地尔硫（ＤＺ）及去乙酰地尔硫（Ｍ１）浓度。以ＳｐｈｅｒｉｓｏｒｂＯＤＳ，５μｍ为层析柱，流动相：甲醇∶乙腈∶水（６０∶１０∶３０），检测波长２３７ｎｍ，以盐酸普罗帕酮为内标。检测范围：ＤＺ为５．４５～２７２．５ｎｇ·ｍｌ－１，Ｍ１为５．８５～２９２．５ｎｇ·ｍｌ－１。最低检测浓度：ＤＺ为２．８７ｎｇ·ｍｌ－１，Ｍ１为１．９９ｎｇ·ｍｌ－１。平均回收率ＤＺ为１０１．８８％，Ｍ１为１０１．７２％，ＲＳＤ均在１２％以内。并对４名受试者口服９０ｍｇ盐酸地尔硫片后，其药时曲线经微机用ＰＫＢＰ－Ｎ１程序拟合，ＤＺ为一房室开放模型，Ｍ１为二房室开放模型，求得ＤＺ和Ｍ１的Ｔ１／２分别为５．６±１．５ｈ和１４±７ｈ。     

两种剂量盐酸地尔硫Chuo缓释胶囊在健康人体药动学及参数相关性

目的研究盐酸地尔硫芯卓缓释胶囊在人体内药动学特性及其两种不同剂量的药动学参数变化规律。方法健康志愿者12名,随机分组,单剂量口服60,120mg盐酸地尔硫芯卓缓释胶囊,采用反相高效液相色谱法测定不同时间的血药浓度,经3P87程序拟合,求算药动学参数。结果60、120mg地尔硫芯卓缓释胶囊在中国健康志愿者体内的药动学参数为Ka(2.2±2.1),(1.6±1.2)h-1;K(0.045±0.0078),(0.054±0.015)h-1;T1/2Ka(0.60±0.36),(0.7±0.4)h;T1/2K(15.8±2.7),(13.9±4.4)h;V(33.2±11.9),(29.8±11.8)L.kg-1;Cl(1.4±0.37),(1.5±0.5)L.h.kg-1;Tmax(4.8±0.9),(4.6±1.0)h;Cmax(28.9±10.8),(65.6±24.8)ng.ml-1;AUC(751.2±211.1),(1487.4±533.1)μg.h.     

Pharmacokinetic changes of diltiazem and desacetyldiltiazem after oral administration of diltiazem in rabbits with diabetes mellitus induced by alloxan

Physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics of drugs used to treat hypertension resulting from diabetic complications. Hence, the pharmacokinetics of diltiazem (DTZ) and its metabolite, desacetyldiltiazem (DAD), were investigated after oral administration of DTZ. DTZ, 20 mg/kg, was orally administered to control rabbits and rabbits with fifth day (experiment was performed at fifth day after first and second days intravenous administration of alloxan) and 13th day (experiment was performed at 13th day after first, second, sixth, and 10th days intravenous administration of alloxan) diabetes mellitus induced by alloxan. Impaired kidney and liver functions were observed in both diabetic groups based on plasma chemistry data and/or tissue microscopy. After oral administration of DTZ, the area under the plasma concentration-time curve from time zero to time infinity were 767, 1280 and 1550 ng h/ml for control rabbits and fifth and 13th days diabetes mellitus rabbits, respectively. The values in diabetes mellitus rabbits were significantly different as compared to control rabbits. The terminal half-lives of DTZ were significantly longer in fifth (13.4 h) and 13th (13.0 h) days diabetes mellitus rabbits than that in control rabbits (8.76 h). The renal clearances of DTZ in fifth (0.3161/h/kg) and 13th (0.2641/h/kg) days diabetes mellitus rabbits were significantly slower than that in control rabbits (0.5051/h/kg), and this could be due to impaired kidney function in the diabetes mellitus rabbits. However, other pharmacokinetic parameters of DAD were not significantly different among three groups of rabbits.     

Pharmacokinetic interaction between cyclosporin and diltiazem

Summary Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng·ml^–1 to 170 ng·ml^–1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng·ml^–1 before to 336 ng·ml^–1.Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitve inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.     

Prediction of In Vivo Interaction Between Triazolam and Erythromycin Based on In Vitro Studies Using Human Liver Microsomes and Recombinant Human CYP3A4

Purpose. To quantitatively predict the in vivo interaction betweentriazolam and erythromycin, which involves mechanism-basedinhibition of CYP3A4, from in vitro studies using human liver microsomes(HLM) and recombinant human CYP3A4 (REC). Methods. HLM or REC was preincubated with erythromycin in thepresence of NADPH and then triazolam was added. - and 4-hydroxy(OH) triazolam were quantified after a 3 min incubation and the kineticparameters for enzyme inactivation (k_inact and K _app) were obtained.Drug-drug interaction in vivo was predicted based on aphysiologically-based pharmacokinetic (PBPK) model, using triazolam anderythromycin pharmacokinetic parameters obtained from the literature and kineticparameters for the enzyme inactivation obtained in the in vitro studies. Results. Whichever enzyme was used, triazolam metabolism was notinhibited without preincubation, even if the erythromycin concentrationwas increased. The degree of inhibition depended on preincubationtime and erythromycin concentration. The values obtained for k_inactand K _app were 0.062 min^–1 and 15.9 M (-OH, HLM), 0.055 min^–1and 17.4 M (4-OH, HLM), 0.173 min^–1 and 19.1 M (-OH, REC),and 0.097 min^–1 and 18.9 M (4-OH, REC). Based on the kineticparameters obtained using HLM and REC, the AUCpo of triazolamwas predicted to increase 2.0- and 2.6-fold, respectively, followingoral administration of erythromycin (333 mg t.i.d. for 3 days), whichagreed well with the reported data. Conclusions. In vivo interaction between triazolam and erythromycinwas successfully predicted from in vitro data based on a PBPK modelinvolving a mechanism-based inhibition of CYP3A4.     

地尔硫卓与美托洛尔在家兔体内的药动学相互作用研究

本文选用６只家兔进行随机交叉实验，对家兔单用地尔硫　、美托洛尔及合用两药时的药动学过程作了比较。发现合用两药后，美托洛尔的Ｋ＿ｅ、Ｃｌ＿ｓ均较单用时小（Ｐ＜０．０５），Ｃ＿ｍａｘ和ＡＵＣ＿（０－∞）则明显增大。地尔硫的Ｋ＿ｅ在合用药时显著增大，其活性代谢物去乙酰地尔硫的Ｃ＿ｍａｘ和ＡＵＣ＿（０－∞）则也有显著提高。表明合用两药后美托洛尔的肝脏代谢受到抑制。本文证实的相互作用提示，临床合用两药时应同时监测患者血浓，并适当调整剂量，以免发生不良反应。     

地尔硫抑制大鼠肝脏药物代谢的机制

目的:研究地尔硫(艹卓)(DZ)抑制大鼠肝脏药物代谢的机制.方法:(1)SD大鼠未诱导或经地塞米松(DEX)、苯巴比妥(PB)、β萘黄酮(BNF)诱导,制备肝微粒体,于DZ体外37℃温孵25min,检测细胞色素P450-Fe(Ⅱ)-代谢物(MI)复合物.(2)未诱导大鼠ip DZ 100mg/kg 3d,或经DEX诱导再给予单剂量DZ 100mg/kg,制备肝微粒体并检测MI复合物.结果:DEX、PB诱导组在体外分别有30.62%和10.30%MI复合物形成.未诱导大鼠ip DZ 3d,体内检测到7.9%MI复合物;经DEX诱导再给予单剂量DZ的大鼠,体内有17.57%MI复合物形成.结论:DZ在大鼠肝脏中经细胞色素P450 3A催化,发生N-去甲基化,生成的活性代谢物可与P450 3A络合而形成MI复合物,使P450 3A丧失部分活性.     

应用地尔硫治疗老年不稳定性心绞痛的疗效观察

目的探讨持续静脉应用地尔硫(合贝爽)治疗老年不稳定性心绞痛(UA)的临床疗效和安全性。方法26例经硝酸甘油治疗效果不佳的老年UA患者用合贝爽30mg加入液体中持续静脉滴注,初始剂量1μg/(kg.m in)-1,若效果欠佳,速度则增至3μg/(kg.m in)-1,直至最大速度5μg/(kg.m in)-1。症状缓解后按有效剂量维持48h后改用合心爽片剂30mg,tid口服。用药过程中观察心绞痛症状、心电图及血流动力学变化。结果26例老年UA患者用药前72h内平均心绞痛发作次数为5.26±2.57次,给予合贝爽治疗后(9.2±6.8)m in时症状缓解;其中7例患者加大合贝爽的剂量至5μg/(kg.m in)-1后心绞痛得到控制。与用药前72h内相比,开始用药48h后心绞痛次数明显减少,每次发作持续时间明显缩短。静滴合贝爽后有3例UA患者异常ST段和T波恢复,6例明显改善;患者血压、心率降低,与基础值相比差异显著(P<0.05),但无急性心肌梗死、死亡等严重不良反应发生。结论对经硝酸甘油治疗效果不佳的老年UA,持续静脉应用合贝爽是一种有效的治疗措施。     

舌下含地尔硫卓的降压作用

高血压病５８例（男性３４例，女性２４例；年龄５４±ｓ１０ａ），采用随机单盲法分２组，其中３０例以国产地尔硫９０ｍｇ舌下含化为治疗组，２８例采用维生素Ｂ１２０ｍｇ舌下含化为对照组。含药后５ｍｉｎ开始观察其降压作用。结果：治疗组于含药后１０，３０，６０和１２０ｍｉｎ时降压总有效率为６０％，９０％，９３％和９３％，而对照组及另外１３名正常人血压均无明显变化。地尔硫含化的缺点为药味苦涩。