甲硝唑对兰索拉唑在大鼠体内药动学的影响

目的:研究甲硝唑在大鼠体内对兰索拉唑药动学特征的影响。方法:通过对兰索拉唑及细胞色素P450酶2C19(CYP2C19)代谢产物5-羟基兰索拉唑和细胞色素P450酶3A4(CYP3A4)代谢产物兰索拉唑砜的血药浓度的测定,计算大鼠体内药动学参数,以甲硝唑联合兰索拉唑用药组与兰索拉唑单独用药组的AUC0-4h比值为指标,研究甲硝唑对大鼠体内兰索拉唑代谢的影响。结果:联用甲硝唑后,兰索拉唑的AUC0-4h降低为单独使用兰索拉唑组的(0.20±0.06)倍(P<0.05)。甲硝唑显著增加5-羟基兰索拉唑与兰索拉唑AUC0-4h的比值,从(0.24±0.08)增至(0.39±0.19)(P<0.05)。结论:甲硝唑在大鼠体内对兰索拉唑CYP3A4主导的磺化代谢抑制作用不明显,对CYP2C19主导的羟化代谢途径可能有诱导作用。     

环孢素A对银杏内酯B大鼠体内药动学的影响

研究环孢素A (cyclosporine A, CyA) 对大鼠静脉注射中药成分银杏内酯B (ginkgolide B, GB) 药动学的影响, 并进行作用机制研究。实验建立了测定大鼠血浆、脑组织和尿液中GB浓度的LC-MS方法, 研究了CyA对GB在大鼠体内血药浓度、脑分布和肾排泄的影响。结果表明静脉注射CyA (10及20 mg·kg⁻¹) 可以显著增加GB的AUC_{0−360 min} (P < 0.01), 降低其CL (P < 0.001); 静脉注射CYP3A抑制剂伊曲康唑 (itraconazole, ICZ) 则对GB的药动学行为无影响。脑分布结果显示, 高、中、低剂量的CyA均可增加GB在脑中的浓度, 此作用具有浓度和时间依赖性, 在5 min时不同剂量的CyA均可显著增加GB在脑中的分布 (P < 0.001), 但在20及60 min时仅高剂量CyA组可显著增加GB脑中的浓度 (P < 0.01及P < 0.001)。不同P-gp抑制剂均可减少GB的肾排泄, 其中CyA (20 mg·kg⁻¹) 组、维拉帕米 (verapamil, VER) 组及地高辛 (digoxin, DGX) 组GB 8 h累积排泄百分率仅分别为对照组的34.8% (P < 0.001)、59.4% (P < 0.001) 及79.7% (P < 0.05); 而ICZ组则无此作用。大鼠静脉给予P-gp抑制剂CyA可以显著提高GB的血药浓度, 减少肾脏对GB排泄且能增加GB在脑中的分布。     

1-(4-溴苄基)-1-(4-溴苄氧基)脲药代动力学和体外代谢的研究

目的研究1-(4-溴苄基)-1-(4-溴苄氧基)脲(HY-D11)在大鼠体内药代动力学过程及其在大鼠肝脏中的代谢途径。方法建立HY-D11的UV-HPLC生物样本检测方法,灌胃给予HY-D11 66.7 mg·kg-1后,观察HY-D11在大鼠体内的药代动力学过程。研究CYP1A抑制剂(α-萘黄酮)、CYP2B抑制剂(舍曲林)、CYP2C抑制剂(槲皮素)、CYP2D抑制剂(育亨宾)、CYP2E抑制剂(双硫仑)及CYP3A抑制剂(醋竹桃霉素)对HY-D11在大鼠肝微粒体温孵液中代谢的影响。结果 HY-D11在大鼠体内的药代动力学过程符合二室模型。药代动力学参数t max为(3.67±0.52)h,C max为(1.61±0.13)mg·L-1,t1/2z为(3.41±3.91)h,平均滞留时间MRT0-∞为(7.05±0.29)h。HY-D11在大鼠微粒体温孵液中呈现明显的酶促动力学特征。醋竹桃霉素组与对照组相比,对HY-D11代谢有明显抑制作用(P<0.01);而与对照组相比,萘黄酮组、舍曲林组、槲皮素组、育亨宾组、双硫仑组对HY-D11的代谢均无抑制作用(P>0.05)。结论 HYD11在大鼠体内吸收、代谢速度较快,在大鼠体内代谢可能主要由CYP3A介导。     

环孢素A-Eudragit S100纳米粒冻干粉制剂在犬体内的药动学

目的:研究环孢素A-Eudragit S100纳米粒冻干粉制剂(freeze-dried cyclosporine A-Eudragit S100 nanoparticles,CyA-S100-NP)在家犬体内药动学及相对生物利用度。方法:以双周期交叉随机试验设计法,高效液相色谱法测定6只家犬口服给予环孢素A-Eudragit S100纳米粒冻干粉硬胶囊和新山地明微乳软胶囊(Neoral)后环孢素A的血药浓度,采用3P97软件计算药动学参数。结果:经3P97软件拟合,环孢素A的药动学过程符合二室模型。与Neoral相比,CyA-S100-NP的AUC显著增大(P<0.05),CL显著降低(P<0.05),相对生物利用度为135.9%。结论:CyA-S100-NP可促进药物口服吸收,显著提高环孢素A的生物利用度,有望开发成为一种新型口服环孢素A纳米粒固体制剂。     

Cocktail探针药物法评价威麦宁胶囊对大鼠体内CYP450活性的影响

目的采用Cocktail探针药物法评价威麦宁胶囊对大鼠体内6种CYP450亚型酶活性的影响。方法分别选用甲苯磺丁脲、氯唑沙宗、茶碱、咪达唑仑、奥美拉唑和右美沙芬作为CYP2C6、CYP2E1、CYP1A2、CYP3A2、CYP2D1和CYP2D2的探针底物。大鼠每日灌胃威麦宁胶囊1.6 g·kg-1,采用LC-MS/MS测定给药前后大鼠体内6种混合探针的血药浓度,计算药动学参数。结果威麦宁胶囊连续给药2周后,与给药前相比,奥美拉唑ρmax、AUC0-t、tmax及AUC0-∞显著升高(P<0.05);咪达唑仑ρmax、AUC0-t和AUC0-∞显著升高(P<0.01或P<0.05);右美沙芬ρmax、AUC0-t升高(P<0.05);甲苯磺丁脲t1/2、AUC0-∞和tmax显著升高(P<0.01或P<0.05),而CL/F显著降低(P<0.01),ρmax、AUC0-t无显著改变(P>0.05);氯唑沙宗ρmax升高(P<0.05),CL/F降低(P<0.05),AUC0-t升高但无显著差异(P>0.05);茶碱ρmax、AUC0-t升高但无显著差异(P>0.05)。表明奥美拉唑、咪达唑仑和右美沙芬代谢明显减慢(均P<0.05),茶碱、甲苯磺丁脲、氯唑沙宗的代谢无显著差异;威麦宁胶囊对大鼠体内CYP2D1、CYP3A2、CYP2D2酶有抑制作用,对CYP1A2、CYP2C6、CYP2E1酶的活性无显著影响。结论当威麦宁胶囊与CYP2C19、CYP3A4、CYP2D6酶的底物药物合用时,需要调整给药剂量,避免因药物相互作用使体内血药浓度过高产生毒副作用。     

贯叶金丝桃对健康受试者体内茶碱药动学的影响[英]／Morimoto T…∥J Clin Pharmacol

贯叶金丝桃由于能诱导细胞色素P450(CYP)3A4和P-糖蛋白(P-gp)而改变某些与之合用药物的药动学参数。考虑到茶碱代谢主要受CYP1A2和部分受CYP2E1与CYP3A4调控，作者采用随机、公开标签和交叉的临床试验，研究了贯叶金丝桃对健康受试者体内茶碱药动学参数的影响。     

联苯双酯与环孢素合用对大鼠肝药物代谢酶的影响

目的:阐明联苯双酯与环孢素合用对药物代谢酶的影响.方法:采用分光光度法测定联苯双酯、环孢素及两者合用时大鼠肝微粒体红霉素N-脱甲基酶(erythromycin demethylase,ERD)、氨基比林Ⅳ-脱甲基酶(aminopyrence N-demethylase,ADM)和谷胱甘肽s转移酶(glutathione S transferenase,GST)的含量或活性.结果:灌胃给药8 d,联苯双酯(200 mg·kg-1)对ADM和GST没有明显诱导作用,但对ERD有显著诱导作用(P<0.01);环孢素(20 mg·kg-1)对ERD和GST没有显著抑制作用(P<0.01);但对ADM有显著抑制作用;联苯双酯与环孢素合用对ADM和GST均有明显抑制作用(P<0.01).结论:BFD是药物代谢酶ERD(CYP3A4)的诱导剂,是ADM(CYP1A1,281,2C11)的抑制剂;BFD与环孢素合用可以抑制ADM(CYP1A1、2B1、2C11)和GST的活性.     

Cocktail探针药物法评价糖尿病大鼠体内细胞色素P450不同亚型的活性

目的:探讨链脲佐菌素(STZ)诱导糖尿病模型大鼠体内细胞色素P450酶(CYPs)6种亚型活性及蛋白含量的变化,为临床合理用药提供参考.方法:将大鼠随机分为空白对照组、糖尿病1周组、4周组和8周组.应用"Cocktail"探针药物法评价各组大鼠血浆中各探针药物的浓度,比较空白对照组和3组糖尿病模型组各探针药物的药动学参数,评价糖尿病大鼠体内细胞色素P450酶亚型1A2、2D6、2C19、2C9、2E1和3A4活性的变化;选择酶联免疫吸附测定法(ELISA)检测糖尿病大鼠肝脏中此6种CYPs亚型酶蛋白相对表达量的变化.结果:相比于空白组,糖尿病4周和8周组大鼠体内咖啡因AUC分别降低了62.78%和79.31%(P<0.01),校正后的清除率(CL Z)分别升高了5.12和52.35倍(P<0.05,P<0.01);糖尿病模型组大鼠体内美托洛尔AUC、t 1/2z和CL Z均无显著变化;糖尿病8周大鼠体内氯唑沙宗AUC降低了60.58%(P<0.01),CL Z升高了1.2倍(P<0.01);糖尿病4周和8周组大鼠体内奥美拉唑AUC降低了55.60%和81.42%(P<0.05,P<0.01),CL Z升高了27.50和41.25倍(P<0.01);8周大鼠甲苯磺丁脲AUC降低了45.39%(P<0.05)、CL Z升高了83.33%(P<0.01);糖尿病1周和8周组大鼠体内咪达唑仑AUC降低了43.23%和53.87%(P<0.05,P<0.01),CL Z升高了1.33和2.04倍(P<0.05).相比于空白组,糖尿病1周和4周组大鼠肝脏中CYP1A2蛋白相对表达量升高了24.60%和26.41%(P<0.05),糖尿病1周组大鼠CYP3A4蛋白相对表达量降低了24.62%(P<0.05),CYP2D6、2E1、2C19和2C9蛋白相对表达量无变化.结论:与空白组相比,糖尿病模型组大鼠体内CYP1A2、2E1、2C19、2C9和3A4活性均被诱导,而CYP2D6活性未发生变化;与空白组相比,糖尿病1周、4周组的大鼠肝脏中CYP1A2蛋白相对表达量明显升高,糖尿病1周组大鼠肝脏中CYP3A4蛋白相对表达量明显降低,CYP2D6、2E1、2C9和2C19亚型酶蛋白相对表达量均未发生显著变化.     

环孢素A的药动学及其影响因素研究进展

目的:对不同人群环孢素A(CSA)的药动学及其主要影响因素进行综述,为临床实施CSA个体化用药方案提供参考。方法:以"Cyclosporine""Pharmacokinetic""Interaction""环孢素A""临床应用"等组合作为关键词,查阅1985-2014年Pub Med、中国医院知识总库等数据库中环孢素的药动学及相关影响因素的文献,并据此进行归纳和总结。结果:共查询到文献1 146条,其中有效文献31条。结果表明,不同年龄、种族、性别、遗传基因型和处于不同机体状态的人群,CSA在其体内的血药浓度、清除率(CL)等药动学参数存在显著差异。胆囊切除、肝硬化、肥胖手术等病理状态和细胞色素P45(0CYP)3A4酶抑制剂、P糖蛋白底物抑制剂联用时,均可升高CSA的血药浓度;促胃肠动力药、CYP3A4酶诱导剂、P糖蛋白底物诱导剂等联用时,可明显降低CSA的血药浓度。结论:CSA的药动学受多种因素影响。在未来的临床工作中,除了应加大CSA的血药浓度监测,还需开展相关基因型多态性的检测技术,以便及时调整CSA的给药剂量,促进临床个体化与合理用药。     

基于CYP3A4酶探讨灯盏花素对洛伐他汀的药动学的影响及机制

目的 探究灯盏花素与洛伐他汀联用对大鼠体内药动学的影响,从代谢酶的角度揭示灯盏花素对洛伐他汀药动学产生影响的机制。方法 采用探针药物法及RT-HPLC法测定咪达唑仑在肝微粒体孵育体系中的浓度,评价灯盏花素与洛伐他汀联用对CYP3A4酶活性的影响。通过RT-PCR反应来检测CYP3A4酶mRNA基因表达,采用Western blot法,从蛋白翻译水平上分析灯盏花素与洛伐他汀联用对大鼠肝脏CYP3A4蛋白表达的影响。结果 洛伐他汀与灯盏花素联合用药后,洛伐他汀在大鼠体内的血药浓度显著升高,从0.39 mg?L-1 上升到1.08 mg?L-1 ,清除率从3.36L?h-1?kg-1降低到1.08L?h-1?kg-1,药物半衰期从5.0h延长到6.2h,联合给药后洛伐他汀的AUC从2.42mg?L-1?h-1上升到4.22mg?L-1?h-1。洛伐他汀组与空白组比较CYP3A4酶活性均没有明显变化;灯盏花素组及灯盏花素联合洛伐他汀组与空白组比较发现均抑制CYP3A4酶活性;灯盏花素与灯盏花素联合洛伐他汀组CYP3A4酶mRNA 表达量均较空白组显著降低;CYP3A4酶蛋白含量结果表明,洛伐他汀组与灯盏花素联合洛伐他汀组与空白组比较CYP3A4酶蛋白含量均没有明显变化。结论 洛伐他汀与灯盏花素联用,灯盏花素通过抑制其基因转录水平抑制CYP3A4的活性,使大鼠体内药动学过程发生变化,洛伐他汀药物的代谢减慢。     

Enhanced Oral Paclitaxel Bioavailability After Administration of Paclitaxel-Loaded Lipid Nanocapsules

Purpose The aim of this study was to evaluate the pharmacokinetics of paclitaxel-loaded lipid nanocapsules (LNC) in rats to assess the intrinsic effect of the dosage form on the improvement of paclitaxel oral exposure. Methods Paclitaxel-loaded LNC were prepared and characterized in terms of size distribution, drug payload, and the kinetics of paclitaxel crystallization. Taxol?, Taxol? with verapamil, or paclitaxel-loaded LNC were administered orally to rats. The plasma concentration of paclitaxel was determined using liquid chromatography mass spectrometry. Results The average size of LNC was 60.9 ± 1.5 nm. The drug payload of paclitaxel was 1.91 ± 0.01 mg/g of aqueous dispersion. The encapsulation efficiency was 99.9 ± 1.0%, and 1.7 ± 0.1% of paclitaxel was crystallized after 24 h. The oral bioavailability of Taxol? alone was 6.5%. After oral administration of paclitaxel-loaded LNC or paclitaxel associated with verapamil, the area under the plasma concentration–time curve was significantly increased (about 3-fold) in comparison to the control group (p < 0.05). Conclusions The results indicated that LNC provided a promising new formulation to enhance the oral bioavailability of paclitaxel while avoiding the use of pharmacologically active P-gp inhibitors, such as verapamil.     

Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors

PURPOSE: The objective of this study was to evaluate the pharmacokinetics of paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration with or without P-glycoprotein (P-gp) inhibitors. METHODS: Paclitaxel SMEDDS formulation was optimized, in terms of droplet size and lack of drug precipitation following aqueous dilution, using a ternary phase diagram. Physicochemical properties of paclitaxel SMEDDS and its resulting microemulsions were evaluated. The plasma concentrations of paclitaxel were determined using a HPLC method following paclitaxel microemulsion administrations at various doses in rats. RESULTS: Following 1:10 aqueous dilution of optimal paclitaxel SMEDDS, the droplet size of resulting microemulsions was 2.0 +/- 0.4 nm, and the zeta potential was -45.5 +/- 0.5 mV. Compared to Taxol, the oral bioavailability of paclitaxel SMEDDS increased by 28.6% to 52.7% at various doses. There was a significant improvement in area under the curve (AUC) and time above therapeutic level (0.1 microM) of paclitaxel SMEDDS as compared to those of Taxol following coadministration of both formulations with 40 mg cyclosporin A (CsA)/kg. The oral absorption of paclitaxel SMEDDS slightly enhanced following coadministration of tacrolimus and etoposide, but plasma drug concentrations did not reach the therapeutic level. The nonlinear pharmacokinetic trend was not modified after paclitaxel was formulated in SMEDDS. CONCLUSIONS: The results indicate that SMEDDS is a promising novel formulation to enhance the oral bioavailability of paclitaxel, especially when coadministered with a suitable P-gp inhibitor, such as CsA.     

An Examination of the Effect of Intestinal First Pass Extraction on Intestinal Lymphatic Transport of Saquinavir in the Rat

Purpose To assess the impact of intestinally based efflux/elimination processes on the extent of intestinal lymphatic transport of saquinavir. To compare the relative effects of co-administration of P-gp/CYP modulators on intestinal lymphatic transport versus systemic bioavailability of saquinavir. Methods A cremophor mixed micelle formulation of saquinavir alone, or co-administered with P-gp/CYP modulators, verapamil, ketoconazole or cyclosporine, was dosed intraduodenally in the mesenteric lymph duct cannulated anaesthetized rat model. Results Co-administration of P-gp/CYP modulators resulted in significant increases in the extent of intestinal lymphatic transport of saquinavir. A comparison of the relative enhancement of lymphatic transport and plasma bioavailability compared to control (i.e. saquinavir alone) reveals a greater effect of verapamil and ketoconazole on the amount of drug transported by the lymphatic route, an observation consistent with a preferential targeting of saquinavir via the intestinal lymphatics. In contrast co-administration of cyclosporine increased both the extent of lymphatic transport (5.5-fold), and systemic bioavailability (4.1-fold). Conclusions Intestinal P-gp/CYP efflux/elimination restricts saquinavir transport via the intestinal lymphatics in the rat. Targeted increases in intestinal lymphatic levels of saquinavir may be achieved by selective inhibition of intestinal P-gp and/or CYP.     

Effects of cysteine on the pharmacokinetics of paclitaxel in rats

Paclitaxel is a P-gp substrate and metabolized via CYP2C and 3A subfamily in rats. It has been reported that cysteine causes the changes in expression of CYP isozymes and intestinal P-gp mediated efflux activity in rats. Thus, the effects of cysteine on the pharmacokinetics of intravenous and oral paclitaxel were investigated in rats. After intravenous administration of paclitaxel (30 mg/kg) to control (CON), single cysteine treatment (ST) and cysteine treatment for a week (CT) rats, the pharmacokinetic parameters were comparable among three groups of rats. Also the pharmacokinetic parameters between CON and ST rats were comparable after oral administration of paclitaxel (30 mg/kg) to rats. These results are consistent with that oral cysteine supplement on a single day did not considerably inhibit the metabolism of paclitaxel via hepatic and/or intestinal CYP3A subfamily and P-gp mediated efflux of paclitaxel in the liver and/or intestine both after intravenous and oral administration to rats. After oral administration of paclitaxel (30 mg/kg) to rats, the greater AUC_{06 h} in CT rats was mainly due to that oral cysteine supplement for seven consecutive days enhanced the gastrointestinal absorption of paclitaxel compared with those in CON and ST rats.     

Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components

AIMS: Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) are both expressed in the intestinal mucosa and present a barrier to oral drug delivery. CYP3A4 and P-gp share both overlapping tissue distribution and substrate specificity. Grapefruit juice interactions with CYP3A4 substrates are well documented and occur as a consequence of down regulation of intestinal CYP3A4. The aim of the present study was to screen grapefruit juice components against the CYP3A4-mediated metabolism and P-gp mediated transport of the HIV-1 protease inhibitor saquinavir. METHODS: Five grapefruit juice components: quercetin, naringin, naringenin, 6', 7'-dihydroxybergamottin and bergamottin were screened as potential inhibitors of the metabolism of saquinavir by human liver microsomes. The known CYP3A4 inhibitor ketoconazole was also screened for inhibitory potential. These compounds were also screened as modulators of P-gp activity by assessing the directional transport of saquinavir across Caco-2 cell monolayers which express P-gp. The effect of verapamil, a known modulator of P-gp function, was also determined in these cell lines. RESULTS: On preincubation, 6', 7'-dihydroxybergamottin and bergamottin inhibited the metabolism of saquinavir, with IC50 values of 0.33+/-0.23 muM and 0.74+/-0.13 muM, respectively (n=3). Ketoconazole achieved an IC50 of 0. 55+/-0.12 muM (n=4). The other compounds studied failed to reach IC50 at concentrations of up to 100 muM. The transport of saquinavir in the basolateral-->apical (BL-->AP) direction exceeded that in the apical -->basolateral direction (AP-->BL), with apparent permeability coefficients of 199.2+/-15.8x10-7 cm s-1 and 8.00+/-1. 13x10-7 cm s-1, respectively (n=3) which is indicative of a polarized efflux mechanism. The ratio of BL-->AP/AP-->BL for saquinavir was 25, but in the presence of verapamil and ketoconazole this ratio was reduced to 3.6 and 4.0, respectively (n=3), indicating extensive inhibition of P-gp mediated saquinavir efflux. Of the grapefruit juice components studied only naringin and 6', 7'-dihydroxybergamottin had any appreciable effect, reducing the ratio to 7.6 and 7.1, respectively (n=3); but this was due solely to increased AP-->BL transport. CONCLUSIONS: Grapefruit juice components inhibit CYP3A4-mediated saquinavir metabolism and also modulate, to a limited extent, P-gp mediated saquinavir transport in Caco-2 cell monolayers. The in vivo effects of grapefruit juice coadministration are most likely the result of effects on CYP3A4 (inhibition and down regulation) and only to a minor extent on modulation of P-gp function.     

Pharmacokinetics of P-glycoprotein inhibition in the rat blood-brain barrier

This article describes the experimental set-up and pharmacokinetic modeling of P-glycoprotein function in the rat blood-brain barrier using [(11)C]verapamil as the substrate and cyclosporin A as an inhibitor of P-gp. [(11)C]verapamil was administered to rats as an i.v. bolus dose followed by graded infusions to obtain steady-state concentrations in the brain during 70 min. CsA was administered as a bolus followed by a constant infusion 20 min after the start of the [(11)C]verapamil infusion. The brain uptake of [(11)C]verapamil over 2 h was portrayed in a sequence of PET scans in parallel with measurement of [(11)C]verapamil concentrations in blood and plasma and CsA concentrations in blood. Mixed effects modeling in NONMEM was used to build a pharmacokinetic model of CsA-induced P-gp inhibition. The brain pharmacokinetics of [(11)C]verapamil was well described by a two-compartment model. The effect of CsA on the uptake of [(11)C]verapamil in the brain was best described by an inhibitory indirect effect model with an effect on the transport of [(11)C]verapamil out of the brain. The CsA concentration required to obtain 50% of the maximal inhibition was 4.9 microg/mL (4.1 microM). The model parameters indicated that 93% of the outward transport of [(11)C]verapamil was P-gp mediated.     

Application of compartmental modeling to an examination of in vitro intestinal permeability data: assessing the impact of tissue uptake, P-glycoprotein, and CYP3A.

P-glycoprotein (P-gp)-mediated drug efflux and cytochrome p450 3A (CYP3A) metabolism within the enterocyte have been implicated as potential biochemical barriers to intestinal drug permeability. The current studies examined the in vitro intestinal permeability of verapamil, a common P-gp and CYP3A substrate, using both disappearance and appearance measurements, and investigated the possible impact of P-gp efflux on the intestinal extraction of verapamil. Bidirectional permeability and metabolism studies were conducted across rat jejunal tissue in side-by-side diffusion chambers and data were modeled using compartmental kinetics. Substantial tissue uptake of verapamil was evident in the in vitro model and resulted in a disappearance permeability coefficient that was approximately 10-fold greater than that determined from verapamil appearance in the receptor chamber. Polarization of the bidirectional transport of verapamil was evident due to P-gp efflux (efflux ratio of 2.5), and significant intestinal extraction of verapamil on passage across the tissue was observed (mucosal to serosal extraction ratio of 0.31 +/- 0.04). Surprisingly, the selective P-gp inhibitor, valspodar (PSC833), had an insignificant impact on P-gp-mediated efflux of verapamil; however, selective CYP3A inhibition (afforded by midazolam) increased mucosal to serosal verapamil transport 1.6-fold, presumably through a reduction in intestinal metabolism. Using a four-compartment model, simulations of the impact of P-gp on the intestinal extraction ratio of verapamil demonstrated that for efflux to increase intestinal extraction, a nonlinear relationship must exist between the extent of drug metabolism and the extent of drug transport; the origin of this "nonlinearity" may include saturable drug metabolism, accumulation, and/or distribution.     

Effects of naringin on the pharmacokinetics of intravenous paclitaxel in rats

It was reported that paclitaxel is an inhibitor of hepatic P-glycoprotein (P-gp) and hepatic microsomal cytochrome P450 (CYP) 3A1/2, and that naringin is an inhibitor of biliary P-gp and CYP3A1/2 in rats. The purpose of this study was to report the effects of oral naringin on the pharmacokinetics of intravenous paclitaxel in rats. Oral naringin (3.3 and 10 mg/kg) was pretreated 30 min before intravenous (3 mg/kg) administration of paclitaxel. After intravenous administration of paclitaxel, the AUC was significantly greater (40.8% and 49.1% for naringin doses of 3.3 and 10 mg/kg, respectively), and Cl was significantly slower (29.0% and 33.0% decrease, respectively) than controls. The significantly greater AUC could be due mainly to an inhibition of metabolism of paclitaxel via CYP3A1/2 by oral naringin. The inhibition of hepatic P-gp by oral naringin could also contribute to the significantly greater AUC of intravenous paclitaxel by oral naringin.     

The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits

We have investigated the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. Pharmacokinetic parameters of verapamil and norverapamil were determined after the oral administration of verapamil (10 mg kg(-1)) to rabbits in the presence and absence of quercetin (5.0 and 15 mg kg(-1)). While co-administration of quercetin concurrently was not effective to enhance the oral exposure of verapamil, pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. Compared with the control group (given verapamil alone), the C(max) and AUC of verapamil increased approximately twofold in the rabbits pretreated with 15 mg kg(-1) quercetin. There was no significant change in T(max) and terminal plasma half-life (t(1/2)) of verapamil in the presence of quercetin. Consequently, absolute and relative bioavailability values of verapamil in the rabbits pretreated with quercetin were significantly higher (P < 0.05) than those from the control group. Metabolite-parent AUC ratio in the rabbits pretreated with quercetin decreased by twofold compared with the control group, implying that pretreatment of quercetin could be effective to inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil. This suggested that concomitant use of quercetin or a quercetin-containing dietary supplement with verapamil requires close monitoring for potential drug interaction.