Effects of diclofenac on the pharmacokinetics of celastrol in rats and its transport

Context: Diclofenac and celastrol are always used together for the treatment of rheumatoid arthritis; the herb–drug interaction potential between diclofenac and celastrol is still unknown.

Objective: This study investigates the effects of diclofenac on the pharmacokinetics of celastrol in rats.

Materials and methods: Twelve male Sprague-Dawley rats were divided into two groups and received celastrol (1?mg/kg) or both celastrol (1?mg/kg) and diclofenac (10?mg/kg) by oral gavage, and blood samples were collected via the oculi chorioideae vein and determined using the LC-MS method developed in this study. Additionally, the effects of diclofenac on the transport of celastrol were investigated using a Caco-2 cell transwell model.

Results: Diclofenac could significantly (p?C_max (from 66.93?±?10.28 to 41.25?±?8.06?ng/mL) and AUC_0-t (from 765.84?±?163.61 to 451.33?±?110.88?μg?×?h/L) of celastrol in rats. The efflux ratio of celastrol increased significantly (p?Discussion and conclusion: These results indicated that diclofenac could decrease the system exposure of celastrol in rats when they are co-administered, and these effects might be exerted via decreasing its absorption in intestine.     

Effects of verapamil on the pharmacokinetics of dihydromyricetin in rats and its potential mechanism

1. This study investigates the effects of verapamil on the pharmacokinetics of dihydromyricetin in rats and clarifies its main mechanism.

2. The pharmacokinetic profiles of oral or intravenous administration of dihydromyricetin in Sprague-Dawley rats with or without pretreatment with verapamil were investigated. In addition, the effects of verapamil on the transport and metabolic stability of dihydromyricetin were investigated using Caco-2 cell transwell model and rat liver microsomes.

3. In the oral group, verapamil could significantly increase C_max, and decrease oral clearance of dihydromyricetin (p?C_max also increased compared with the control group, but the difference was not significant. However, the t_1/2 and clearance rate decreased than that of the control (p?p?P-gp inhibitor, verapamil. Additionally, the intrinsic clearance rate of dihydromyricetin was decreased by the pretreatment with verapamil (27.0 versus 32.5?μL/min/mg protein).

4. Those results indicated that verapamil could significantly change the pharmacokinetic profiles of dihydromyricetin in rats, and it might exert these effects through increasing the absorption of dihydromyricetin by inhibiting the activity of P-gp, or through inhibiting the metabolism of dihydromyricetin in rat liver.     

Effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism

Context: Asiatic acid has been reported to possess a wide range of pharmacological activities.

Objective: This study investigates the effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism.

Materials and methods: The pharmacokinetics of orally administered asiatic acid (20?mg/kg) with or without glycyrrhizin pretreatment (100?mg/kg/day for seven days) were investigated using a LC–MS method. Additionally, the Caco-2 cell transwell model and rat liver microsome incubation systems were used to investigate the potential mechanism of glycyrrhizin’s effects on the pharmacokinetics of asiatic acid.

Results: The results showed that the C_max (221.33?±?21.06 vs. 324.67?±?28.64?ng/mL), AUC_0–inf (496.12?±?109.31 vs. 749.15?±?163.95?μg·h/L) and the t_1/2 (1.21?±?0.27 vs. 2.04?±?0.32?h) of asiatic acid decreased significantly (p?p?Discussion and conclusions: In conclusion, these results indicated that glycyrrhizin could decrease the system exposure of asiatic acid, possibly by inducing the activity of P-gp or CYP450 enzyme.     

The effects of verapamil on the pharmacokinetics of curculigoside in rats

Context: Clarifying the potential mechanism of the poor oral bioavailability of curculigoside would be helpful for for investigating pharmacological effects and clinical applications.

Objective: To clarify the main mechanism for poor oral bioavailability.

Materials and methods: First, the pharmacokinetics of curculigoside (20?mg/kg) in rats with and without pretreatment with verapamil (10?mg/kg) was determined using a sensitive and reliable LC-MS method. Then the effects of verapamil on the transport and metabolic stability of curculigoside were investigated using Caco-2 cell transwell model and rat liver microsome incubation systems.

Results: The results showed that verapamil could significantly increase the peak plasma concentration (from 60.17?ng/mL to 93.66?ng/mL) and AUC_0?t (from 289.57 to 764.02?ng·h/mL) of curculigoside. The Caco-2 cell experiments indicated that the efflux ratio of curculigoside was 3.92 (P_appAB 6.43?±?0.57?×?10?^?7?cm/s; P_appBA 2.52?±?0.37?×?10?^?36?cm/s), P-gp might be involved in the transport of curculigoside, and verapamil could inhibit the efflux of curculigoside and increase the absorption of curculigoside significantly in the Caco-2 cell monolayer. Additionally, the rat liver microsome incubation experiments indicated that verapamil could significantly decrease the intrinsic clearance rate of curculigoside (from 38.8 to 23.6?μL/min/mg protein).

Discussion and conclusion: These results indicated that verapamil could significantly change the pharmacokinetic profiles of curculigoside in rats, the poor absorption due to P-gp mediated efflux in intestine and high intrinsic clearance rate in rat liver may be the main reason for the poor oral absolute bioavailability of curculigoside.     

Effects of glycyrrhizin on the pharmacokinetics of puerarin in rats

1. Puerarin has been reported to possess a wide range of pharmacological activities. This study investigated the effects of glycyrrhizin on the pharmacokinetics of puerarin in rats.

2. The pharmacokinetics of orally administered puerarin (50?mg/kg) with or without glycyrrhizin pretreatment (100?mg/kg/day for 7?days) were investigated. The plasma concentration of puerarin was determined using a sensitive and reliable LC-MS/MS method. The pharmacokinetics profiles were calculated and compared. Additionally, a Caco-2 cell transwell model was used to investigate the potential mechanism of glycyrrhizin’s effects on the pharmacokinetics of puerarin.

3. The results showed that when the rats were pretreated with glycyrrhizin, the maximum concentration (C_max) of puerarin decreased from 761.25?±?52.34 to 456.32?±?34.75?ng/mL, and the area under the concentration–time curve from zero to infinity (AUC_0–inf) also decreased from 4142.15?±?558.51 to 2503.74?±?447.57?μg·h/L. The oral clearance of puerarin increased significantly from 12.20?±?1.53 to 20.47?±?3.25?L/h/kg (p?4. In conclusion, these results indicated that glycyrrhizin could affect the pharmacokinetics of puerarin, possibly by decreasing the systemic exposure of puerarin by inducing the activity of P-gp.     

The effects of triptolide on the pharmacokinetics of sorafenib in rats and its potential mechanism

Context: Combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatment. However, their herb–drug interaction remains unknown.

Objective: This study investigates the herb–drug interaction between triptolide and sorafenib.

Materials and methods: The effects of triptolide (10?mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100?mg/kg) in rats, and blood samples were collected within 48?h and evaluated using LC-MS/MS. The effects of triptolide on the absorption and metabolism of sorafenib were also investigated using Caco-2 cell monolayer model and rat liver microsome incubation systems.

Results: The results showed that the C_max (low dose: 72.38?±?8.76 versus 49.15?±?5.46?ng/mL; medium dose: 178.65?±?21.05 versus 109.31?±?14.17?ng/mL; high dose: 332.81?±?29.38 versus 230.86?±?9.68?ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t_1/2 of sorafenib increased significant (p?Discussion and conclusions: These results indicated that triptolide could change the pharmacokinetic profiles of sorafenib in rats; these effects might be exerted via decreasing the intrinsic clearance rate of sorafenib in rat liver.     

Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism

ContextRotundic acid (RA), a plant-derived pentacyclic triterpene acid, has been reported to possess extensive pharmacological activities. The poor bioavailability limits its further development and potential clinic application.ObjectiveTo clarify the potential mechanism for poor oral bioavailability.Materials and methodsThe single-dose pharmacokinetics of orally administered RA (10 mg/kg) in Sprague–Dawley rats without or with verapamil (25 or 50 mg/kg) were investigated. Additionally, MDCKII-MDR1 and Caco-2 cell monolayers, five recombinant human cytochrome P450 (rhCYP) enzymes (1A2, 2C8, 2C9, 2D6 and 3A4), and rat liver microsomes were also conducted to investigate its potential mechanism.ResultsVerapamil could significantly affect the plasma concentration of RA. Co-administered verapamil at 25 and 50 mg/kg, the AUC_0–∞ increased from 432 ± 64.2 to 539 ± 53.6 and 836 ± 116 ng × h/mL, respectively, and the oral clearance decreased from 23.6 ± 3.50 to 18.7 ± 1.85 and 12.2 ± 1.85 L/h/kg, respectively. The MDCKII-MDR1 cell assay showed that RA might be a P-gp substrate. The rhCYPs experiments indicated that RA was mainly metabolized by CYP3A4. Additionally, verapamil could increase the absorption of RA by inhibiting the activity of P-gp, and slow down the intrinsic clearance of RA from 48.5 ± 3.18 to 12.0 ± 1.06 µL/min/mg protein.Discussion and conclusionsThese findings indicated that verapamil could significantly affect the pharmacokinetic profiles of RA in rats. It was demonstrated that P-gp and CYP3A were involved in the transport and metabolism of RA, which might contribute to the low oral bioavailability of RA.     

Effects of ginkgo leaf tablet on the pharmacokinetics of rosiglitazone in rats and its potential mechanism

ContextGinkgo leaf tablet (GLT), a traditional Chinese herbal formula, is often combined with rosiglitazone (ROS) for type 2 diabetes mellitus treatment. However, the drug-drug interaction between GLT and ROS remains unknown.ObjectiveTo investigate the effects of GLT on the pharmacokinetics of ROS and its potential mechanism.Materials and methodsThe pharmacokinetics of 10 mg/kg ROS with 100/200 mg/kg GLT as single-dose and 10-day multiple-dose administration were investigated in Sprague-Dawley rats. In vitro, the effects of GLT on the activity of CYP2C8 and CYP2C9 were determined in recombinant human yeast microsomes and rat liver microsomes with probe substrates.ResultsThe t_1/2 of ROS increased from 2.14 ± 0.38 (control) to 2.79 ± 0.37 (100 mg/kg) and 3.26 ± 1.08 h (200 mg/kg) in the single-dose GLT administration. The AUC_0-t (139.69 ± 45.46 vs. 84.58 ± 39.87 vs. 66.60 ± 15.90 h·μg/mL) and t_1/2 (2.75 ± 0.70 vs. 1.99 ± 0.44 vs. 1.68 ± 0.35 h) decreased significantly after multiple-dose GLT treatment. The IC₅₀ values of quercetin, kaempferol, and isorhamnetin, GLT main constituents, were 9.32, 7.67, and 11.90 μmol/L for CYP2C8, and 27.31, 7.57, and 4.59 μmol/L for CYP2C9. The multiple-dose GLT increased rat CYP2C8 activity by 44% and 88%, respectively.Discussion and conclusionsThe metabolism of ROS is attenuated in the single dose of GLT by inhibiting CYP2C8 and CYP2C9 activity, and accelerated after the multiple-dose GLT treatment via inducing CYP2C8 activity in rats, indicating that the clinical dose of ROS should be adjusted when co-administrated with GLT.     

Effects of verapamil on the pharmacokinetics of puerarin in rats

Abstract

1. The oral bioavailability of puerarin is poor which hindered its clinical performance.

2. This study investigates the effects of verapamil on the pharmacokinetics of puerarin in rats.

3. The pharmacokinetics of orally administered puerarin (50?mg/kg) with or without verapamil pretreatment (10?mg/kg/day for 7?days) were investigated. The plasma concentration of puerarin was determined using LC-MS/MS method, and the pharmacokinetics profiles were calculated and compared. Caco-2 cell transwell model was also used to investigate the effects of verapamil on the transport pf puerarin.

4. The results showed that when the rats were pretreated with verapamil, the maximum concentration (C_max) of puerarin increased from 683.7?±?51.2 to 933.5?±?75.8?ng/mL (p?<?0.05), and the area under the concentration-time curve from zero to infinity (AUC_0-inf) also increased from 3687.3?±?444.6 to 5006.1?±?658.6?μg·h/L (p?<?0.05). The Caco-2 cell transwell experiments indicated that verapamil could decrease the efflux ratio of puerarin from 1.90 to 1.19 through inhibiting the activity of P-gp.

5. In conclusion, these results indicated that verapamil could affect the pharmacokinetics of puerarin, possibly by increasing the systemic exposure of puerarin by inhibiting the activity of P-gp.

     

Pharmacokinetic study on the interaction between pachymic acid and bavachin and its potential mechanism

ContextPachymic acid and bavachin are commonly used drugs in the therapy of lung cancer.ObjectiveThe co-administration of pachymic acid and bavachin was investigated to evaluate their potential drug-drug interaction.Materials and methodsThe pharmacokinetics of bavachin (10 mg/kg) was studied in male Sprague-Dawley (SD) rats in the presence of pachymic acid (5 mg/kg) (n = 6). The rats without pre-treatment of pachymic acid were set as the control and the pre-treatment of pachymic acid was conducted for 7 days before the administration of bavachin. The effect of pachymic acid on the activity of CYP2C9 was also estimated in rat liver microsomes with corresponding probe substrates.ResultsPachymic acid influenced the pharmacokinetic profile of bavachin with the increased AUC (32.82 ± 4.61 vs. 19.43 ± 3.26 μg/L/h), the prolonged t_1/2 (3.21 ± 0.65 vs. 2.32 ± 0.28 h), and the decreased CLz/F (307.25 ± 44.35 vs. 523.81 ± 88.67 L/h/kg) in vivo. The metabolic stability of bavachin was enhanced by pachymic acid and the transport of bavachin was inhibited by pachymic acid. Pachymic acid was found to inhibit the activity of CYP2C9 with the IC₅₀ of 21.25 µM as well as the activity of P-gp.Discussion and conclusionThe interaction between pachymic acid and bavachin results from the inhibition of CYP2C9 and P-gp. The dose of bavachin should be adjusted when combining with pachymic acid. The study design can be generalized to a broader study population with adjustment in the dose.     

Effects of astragaloside IV on the pharmacokinetics of puerarin in rats

Abstract

1. Radix astragali and puerarin are always used together for cardiovascular disease in China clinics.

2. This study investigates the effects of astragaloside IV (AS-IV, the main components of radix astragali) on the pharmacokinetics of puerarin in rats.

3. The pharmacokinetics of orally administered puerarin (50?mg/kg) with or without AS-IV pretreatment (100?mg/kg/day for seven days) were investigated. The plasma concentration of puerarin was determined using LC–MS/MS method, and the pharmacokinetics profiles were calculated and compared. Caco-2 cell transwell model was also used to investigate the effects of AS-IV on the transport pf puerarin.

4. The results showed that when the rats were pretreated with AS-IV, the maximum concentration (C_max) of puerarin decreased from 760 to 467?ng/mL (p?<?.05, n?=?6, 90% CI, 293?±?61.28), and the area under the concentration-time curve from zero to infinity (AUC_0–inf) also decreased from 4097 to 2330?μg·h/L (p?<?.05, n?=?6). The oral clearance of puerarin increased significantly from 11.9 to 22.4?L/h/kg (p?<?.05, n?=?6). The Caco-2 cell transwell experiments indicated that AS-IV could increase the efflux ratio of puerarin from 1.81 to 2.79 through inducing the activity of P-gp.

5. In conclusion, these results indicated that AS-IV could affect the pharmacokinetics of puerarin, possibly by decreasing the systemic exposure of puerarin by inducing the activity of P-gp.

     

Effects of berberine on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism

Context: Losartan and berberine (BBR) are often simultaneously used for the treatment of senile diabetic nephropathy in clinics. However, the potential herb–drug interaction between losartan and BBR is unknown.

Objective: This study investigates the influence of BBR on the pharmacokinetics of losartan and EXP3174, and investigates the effects of BBR on the metabolic stability of losartan.

Materials and methods: The pharmacokinetic profiles losartan and EXP3174 of orally administered losartan (10?mg/kg) with and without pretreatment with BBR (20?mg/kg) within 24?h were determined in Sprague-Dawley rats. The inhibitory effects of BBR on the metabolic stability of losartan were investigated using rat liver microsomes.

Results: The C_max (1.26?±?0.37 versus 1.96?±?0.45?mg/L) and the AUC_(0–t) (8.25?±?0.89 versus 12.70?±?1.42?mg h/L) of losartan were significantly (p?<?0.05) increased by BBR compared to the control, while the C_max (0.97?±?0.15 versus 0.77?±?0.06?mg/L) of EXP3174 was significantly decreased compared to the control (p?<?0.05). The T_max of losartan was prolonged from 0.41?±?0.12 to 0.52?±?0.18?h, but the difference was not significant. However, the T_max of EXP3174 was decreased significantly (p?<?0.05) from 8.14?±?0.36 to 3.33?±?0.28?h. The metabolic stability of losartan was increased from 37.4 to 59.6?min.

Discussion and conclusion: We infer that BBR might increase the plasma concentration of losartan and decrease the concentration of EXP3174 through inhibiting the activity of CYP3A4 or CYP2C9.     

甘草甜素对实验性肥胖大鼠减肥作用及机制探讨

目的探讨甘草甜素（glycyrrhizin）的减肥作用及其可能的作用机制。方法高脂饮食诱导肥胖大鼠模型,通过测量体重、Lee＇s指数、腹腔脂肪分布及重量、摄食量、血脂和血糖,检验甘草甜素灌服4周后的减肥效果;体外培养诱导分化3T3-L1前脂肪细胞,观察药物对脂肪细胞增殖,脂质合成和分解的影响。结果甘草甜素能显著降低高脂饮食诱导的肥胖大鼠体重和Lee’s指数,使其腹腔脂肪减少,降低血液中胆固醇（TC）和游离脂肪酸（FFA）含量,抑制前脂肪细胞增殖,促进脂肪分解,减少甘油三酯（TG）堆积。结论甘草甜素有显著的减肥和调血脂作用,其可能的机制是抑制前脂肪细胞增殖和分化,促进细胞内脂肪分解,降低脂肪细胞内TG存储量。     

Effects of Danshen tablets on pharmacokinetics of atorvastatin calcium in rats and its potential mechanism

Context: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with atorvastatin calcium (AC) for treating coronary heart disease in the clinic.

Objective: This study investigated the effects of DST on the pharmacokinetics of AC and the potential mechanism.

Materials and methods: The pharmacokinetics of AC (1?mg/kg) with or without pretreatment of DST (100?mg/kg) were investigated using LC-MS/MS. The effects of DST (50?μg/mL) on the metabolic stability of AC were also investigated using rat liver microsome incubation systems.

Results: The results indicated that C_max (23.87?±?4.27 vs. 38.94?±?5.32?ng/mL), AUC_(0–t) (41.01?±?11.32 vs. 77.28?±?12.92?ng h/mL), and t_1/2 (1.91?±?0.18 vs. 2.74?±?0.23?h) decreased significantly (p?t_1/2) of AC was also decreased (25.7?±?5.2 vs. 42.5?±?6.1) with the pretreatment of DST.

Discussion and conclusions: This study indicated that the main components in DST could accelerate the metabolism of AC in rat liver microsomes and change the pharmacokinetic behaviors of AC. So these results showed that the herb-drug interaction between DST and AC might occur when they were co-administered. Therefore, the clinical dose of AC should be adjusted when DST and AC are co-administered.     

辛伐他汀对厄贝沙坦药代动力学影响的研究

目的探讨辛伐他汀相同剂量(5 mg·kg-1)诱导不同时间(3 d和5 d)对新西兰大白兔体内厄贝沙坦药代动力学的影响。方法 24只新西兰大白兔随机分为4组,分别是:3 d对照组(以2%羧甲基纤维素溶液为对照,单用厄贝沙坦50 mg·kg-1)、5 d对照组(以2%羧甲基纤维素溶液为对照,单用厄贝沙坦50 mg·kg-1)、辛伐他汀3 d和辛伐他汀5d诱导组。采用HPLC-荧光法测定血药浓度,DAS3.0软件进行数据处理,计算药代动力学参数。Cmax和Tmax为实验测得。主要药代动力学参数用SPSS13.0软件包进行统计分析。结果经统计分析,与相应对照组比较,辛伐他汀3 d诱导组厄贝沙坦在兔体内的主要药代参数如AUC、CL、Cmax、T 12等差异无显著性(P>0.05);而辛伐他汀5 d诱导组的主要药代参数AUC(0-36)、AUC(0-∞)、MRT(0-36)、MRT(0-∞)、Cmax明显增加(P<0.05),CL明显降低(P<0.05);辛伐他汀5 d诱导组与辛伐他汀3 d诱导组相比,其主要药代参数AUC(0-36)、AUC(0-∞)、MRT(0-36)、MRT(0-∞)、Cmax增加(P<0.05),CL降低(P<0.05)。结论辛伐他汀诱导3 d对新西兰大白兔体内厄贝沙坦的药代动力学无影响;辛伐他汀诱导5 d明显影响新西兰大白兔体内厄贝沙坦的药代动力学;与辛伐他汀3 d诱导组比,辛伐他汀5 d诱导对新西兰大白兔体内厄贝沙坦的药代动力学影响明显。     

Effects of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats

1. This study investigates the influence of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats.

2. The pharmacokinetic profiles of losartan and EXP3174 of orally administered losartan (10?mg/kg) with or without pretreatment with quercetin (20?mg/kg/day for 7 days) were investigated. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism.

3. The results showed that when the rats were pretreated with quercetin, the C_max (2.16?±?0.40 vs. 1.33?±?0.21?mg/L) and the AUC_(0–t) (13.89?±?1.22 vs. 7.34?±?0.75?mg·h/L) of losartan increased significantly (p?<?.05), and while the C_max (0.76?±?0.09 vs. 1.14?±?0.18?mg/L) of EXP3174 decreased significantly compared to the control (p?<?.05). The t_1/2 of losartan was prolonged from 3.27?±?0.45?h to 4.74?±?0.51?h (p?<?.05). The results also indicated that quercetin could increase losartan absorption rate by inhibiting the activity of P-gp and decrease its metabolic stability by inhibiting the activity of CYP450 enzyme.

4. These results indicated that the herb–drug interaction between quercetin and losartan might occur when they are co-administered in rats, quercetin could increase the systemic exposure of losartan and decrease the plasma concentration of EXP3174, possibly by inhibiting the activity of P-gp or CYP450 enzyme.     

The drug–drug interaction of sorafenib mediated by P-glycoprotein and CYP3A4

1.?The aim of this study was to investigate the potential drug–drug interaction of sorafenib mediated by P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4).

2.?In this research, a sensitive and reliable LC-MS/MS method was developed and applied for the determination of sorafenib in rat plasma. The pharmacokinetic profiles of orally administered sorafenib from rats with and without verapamil pretreatment were investigated.

3.?The results indicated that when the rats were pretreated with verapamil, the C_max of sorafenib increased from 55.73?ng/ml to 87.72?ng/ml (57.40%), and the AUC_(0?t) increased by approximately 58.2% when sorafenib was co-administered with verapamil. Additionally, the effects of verapamil on the absorption of sorafenib were investigated using the Caco-2 cell transwell model, and the effects of verapamil on the metabolic stability of sorafenib were also studied using rat liver microsomes incubation systems. A markedly higher transport of sorafenib across the Caco-2 cells was observed in the basolateral-to-apical direction and was abrogated in the presence of the P-gp inhibitor, verapamil. The results indicated that P-gp was involved in the transport of sorafenib, and verapamil could increase its absorption in the Caco-2 cell model, and the metabolic stability of sorafenib was prolonged by the pretreatment with verapamil.

4.?In conclusion, the drug–drug interaction of sorafenib might happen when sorafenib was co-administered with P-gp or CYP3A4 inhibitors.     

克拉霉素对兰索拉唑及其代谢产物在大鼠体内药动学特征的影响

目的研究克拉霉素对兰索拉唑及其代谢产物5-羟基兰索拉唑和兰索拉唑砜药动学特征的影响。方法 24只大鼠随机分为4组,分别十二指肠给予兰索拉唑(8 mg·kg^-1)+生理盐水、兰索拉唑(8 mg·kg^-1)+酮康唑(5 mg·kg^-1)、兰索拉唑(8 mg·kg^-1)+反苯环丙胺(5 mg·kg^-1)、兰索拉唑(8 mg·kg^-1)+克拉霉素(8 mg·kg^-1)。于给药后不同时间点采集血样,用LC-MS/MS法测定药物浓度。通过对兰索拉唑及5-羟基兰索拉唑和兰索拉唑砜血药浓度的测定,计算大鼠体内药动学参数。以5-羟基兰索拉唑、兰索拉唑砜与兰索拉唑AUC_0→4h的比值分别作为原药经CYP2C19和CYP3A4代谢程度的指标,研究克拉霉素对兰索拉唑代谢的影响。结果克拉霉素显著增加兰索拉唑的AUC_0→4h、MRT和t_1/2,显著降低其CLz。克拉霉素显著降低兰索拉唑砜与兰索拉唑AUC_0→4h的比值,从0.63±0.17降至0.15±0.09（P<0.05）,兰索拉唑砜的ρ_max显著降低,MRT和t_1/2显著延长。克拉霉素对5-羟基兰索拉唑的药动学参数无明显影响。结论克拉霉素在大鼠体内对兰索拉唑CYP3A4主导的磺化代谢抑制作用明显,可明显增加兰索拉唑的生物利用度,对临床治疗消化性溃疡有积极意义。     

LC-MS测定雷公藤甲素及其在Caco-2细胞上的转运特征

目的：建立体外模拟体内肠道细胞的Caco-2细胞Transwell模型,以此研究雷公藤甲素在Caco-2细胞模型上的跨膜转运特征。方法：采用聚酯碳酸酯膜连续培养Caco-2细胞21天,形成致密的单层细胞模型。然后对影响雷公藤甲素在Caco-2细胞模型上转运特征的因素包括浓度、时间及跨膜转运蛋白（P-糖蛋白,多药耐药蛋白,乳腺癌耐药蛋白）进行考察;同时采用LC-MS对溶液中的雷公藤甲素的含量进行测定。结果：雷公藤甲素主要以主动转运的方式进行吸收,且随着时间和药物浓度的增加,转运量明显增加。结论：雷公藤甲素在Caco-2细胞上转运存在一定的浓度及时间依赖性,且P-gp介导雷公藤甲素在Caco-2细胞上转运。