The oral bioavailability of puerarin is poor which hindered its clinical performance.
This study investigates the effects of verapamil on the pharmacokinetics of puerarin in rats.
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.
The results showed that when the rats were pretreated with verapamil, the maximum concentration (Cmax) 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 (AUC0-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.
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.
The objective of this study was to investigate the effect of concomitantly administered silymarin on the pharmacokinetics of talinolol, a typical substrate for P-glycoprotein (P-gp), in healthy Chinese volunteers and its association with a multidrug resistance 1 (MDR1) C3435T genetic polymorphism.
Eighteen healthy adult men (six MDR1 3435CC homozygotes, six MDR1 3435CT heterozygotes and six MDR1 3435TT homozygotes) were recruited in a two-phase, randomized, single-blind, crossover design. The pharmacokinetics of talinolol were measured after co-administration of placebo or 140?mg silymarin capsules three times daily for 14 days. Concentrations of talinolol in plasma were measured for up to 36?h after drug administration by liquid chromatography-mass spectrometry (HPLC-MS).
The peak plasma concentration (Cmax) of talinolol was significantly higher after silymarin administration as compared with placebo (p?=?0.007). The area under the plasma concentration–time curve from zero to 36?h (AUC0–36) and AUC0–∞ of talinolol was increased by 36.2% ± 33.2% and 36.5% ± 37.9%, respectively, by silymarin co-administration. The oral clearance (CL/F) of talinolol was decreased by 23.1% ± 16.6% (p?tmax) and the blood elimination half-life (t1/2) of talinolol was observed between the placebo- and silymarin-treated phases.
Co-administration of silymarin significantly increased the plasma concentration of talinolol in healthy volunteers.
This study investigates the effect of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea, on the pharmacokinetics of amlodipine in rats.
The pharmacokinetics of orally administered amlodipine (1?mg/kg) with or without EGCG pretreatment (30?mg/kg/day for 10?days) were investigated. Plasma concentrations of amlodipine were determined by using a sensitive and reliable liquid chromatography with tandem mass spectroscopy (LC-MS/MS) method. The effects of EGCG on the metabolic stability of amlodipine were investigated by using rat liver microsome incubation systems.
The results indicated that when the rats were pretreated with EGCG, the Cmax of amlodipine increased from 16.32?±?2.57 to 21.44?±?3.56?ng/mL (p?<?0.05), the Tmax decreased from 5.98?±?1.25 to 4.01?±?1.02?h (p?<?0.05), and the AUC0–t increased from 258.12?±?76.25 to 383.34?±?86.95?μg h L?1 (p?<?0.05), which suggested that the pharmacokinetic behavior of amlodipine was affected after oral co-administration of EGCG. Additionally, the metabolic half-life was prolonged from 31.3?±?5.6 to 52.6?±?7.9?min (p?<?0.05) with the pretreatment of EGCG.
It can be speculated that the drug-drug interaction between EGCG and amlodipine might occur, which might have resulted from the metabolism inhibition of amlodipine by EGCG when they were co-administered.
Aconite alkaloids are the main bioactive ingredients existing in Aconitum, for instance aconitine (AC), which exhibit potent analgesic, antirheumatic and other pharmacological effects. In this study, effects of long-term treatment with liquorice on pharmacokinetics of AC in rats were investigated.
Pharmacokinetics of AC after oral administration of AC at 1.5?mg/kg either with pre-treatment of liquorice water extracts at 0.433 or 1.299?g/kg (crude drug), respectively, for one week or not were studied. Additionally, LS-180 cells and human primary hepatocytes were utilized to explore the potential effects of bioactive ingredients of liquorice on P-glycoprotein (P-gp) and Cytochromes P450 (CYPs), respectively.
The results revealed that exposure of AC after pre-treatment with liquorice was altered remarkably. Area under the concentration-time curve (AUC) decreased from 161?±?37.8 to 58.8?±?8.97 and 44.7?±?8.20?ng/mL*h, respectively. Similarly, Cmax decreased from 26.2?±?5.19 to 11.8?±?1.15 and 6.86?±?0.600?ng/mL, respectively. In addition, expressions of CYPs of human primary hepatocytes were enhanced to various contents after induction. Moreover, accumulation of AC and hypaconitine (HA), not mesaconitine (MA) inside of LS-180 cells were reduced after pre-treatment by comparison with control.
In conclusion, the exposure of AC in vivo declined after pre-treatment with liquorice extract, which may be highly associated with upregulated expression and/or function of CYPs and P-gp.
Radix astragali and puerarin are always used together for cardiovascular disease in China clinics.
This study investigates the effects of astragaloside IV (AS-IV, the main components of radix astragali) on the pharmacokinetics of puerarin in rats.
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.
The results showed that when the rats were pretreated with AS-IV, the maximum concentration (Cmax) 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 (AUC0–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.
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.
Triptolide and fenofibrate are often used together for the treatment of nephrotic syndrome in Chinese clinics.
This study investigates the effects of triptolide on the pharmacokinetics of fenofibrate in rats and it potential mechanism.
The pharmacokinetics of fenofibrate (20?mg/kg) with or without triptolide pretreatment (2?mg/kg/day for seven days) were investigated. Additionally, the inhibitory effects of triptolide on the metabolic stability of fenofibrate were investigated using rat liver microsome incubation systems.
The results indicated that the Cmax (35.34?±?7.52 vs. 30.43?±?6.45?μg/mL), t1/2 (6.17?±?1.15 vs. 4.90?±?0.82?h) and AUC(0–t) (468.12?±?35.84 vs. 416.35?±?32.68?mg?h?L?1) of fenofibric acid decreased significantly (p?<?.05). The Tmax of fenofibric acid increased significantly (p?<?.05) from 5.12?±?0.36 to 6.07?±?0.68?h. Additionally, the metabolic stability of fenofibrate was prolonged from 35.8?±?6.2 to 48.6?±?7.5?min (p?<?.05) with the pretreatment of triptolide.
In conclusion, these results indicated that triptolide could affect the pharmacokinetics of fenofibric acid, possibly by inhibiting the metabolism of fenofibrate in rat liver when they were co-administered.
The present study was designed to investigate the multiple-dosing pharmacokinetics of antimalarial drugs artemether (ARM), artesunate (ARS), and their metabolite dihydroartemisinin (DHA) in rats.
Rats were randomized into four groups. Two groups of rats received oral doses of ARM or ARS once daily for five consecutive days. And another two groups of rats were given a single oral dose of ARM or ARS. Plasma samples were analysed for artemisinin drugs and their active metabolite DHA, using a validated liquid chromatography/tandem mass spectrometric (LC/MS/MS) method.
ARM and ARS could be biotransformed to metabolite DHA almost immediately after oral administration to rats. The area under the plasma concentration–time curve (AUC0–t) of ARM after 5-day oral doses significantly decreased from 50.3 to 23.4 ng×h/mL (P?<?0.05), and oral clearance (CL/F) of ARM increased from 10.5 to 27.2?L/min/kg (P?<?0.05). The AUC0–t of its metabolite DHA of ARM significantly decreased from 42.1 to 16.4 ng×h/mL (P?<?0.05), and its CL/F increased from 11.7 to 33.4?L/min/kg (P?<?0.05). The 5-day oral doses of ARS did not result in significant changes (P?>?0.05) in pharmacokinetic parameters of ARS, whereas its metabolite DHA exhibited lower AUC (P?=?0.05), compared with that obtained after a single oral administration.
The results showed ARM and its metabolite DHA exhibited time-dependent pharmacokinetic characteristics with decreased plasma drug level after five consecutive days of oral administration to rats, whereas ARS and its metabolite DHA did not show similar characteristics.
Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active metabolites is CYP mediated. This study compared the efficiency, in vivo, of the formation of prasugrel and clopidogrel thiolactones and their active metabolites.
The areas under the plasma concentration versus time curve (AUC) of the thiolactone intermediates in the portal vein plasma after an oral dose of prasugrel (1 mg kg?1) and clopidogrel (0.77 mg kg?1) were 15.8 ± 15.9 ng h ml?1 and 0.113 ± 0.226 ng h ml?1, respectively, in rats, and 454 ± 104 ng h ml?1 and 23.3 ± 4.3 ng h ml?1, respectively, in dogs, indicating efficient hydrolysis of prasugrel and little metabolism of clopidogrel to their thiolactones in the intestine.
The relative bioavailability of the active metabolites of prasugrel and clopidogrel calculated by the ratio of active metabolite AUC (prodrug oral administration/active metabolite intravenous administration) were 25% and 7%, respectively, in rats, and 25% and 10%, respectively, in dogs.
Single intraduodenal administration of prasugrel showed complete conversion of prasugrel, resulting in high concentrations of the thiolactone and active metabolite of prasugrel in rat portal vein plasma, which demonstrates that these products are generated in the intestine during the absorption process.
In conclusion, the extent of in vivo formation of the thiolactone and the active metabolite of prasugrel was greater than for clopidogrel’s thiolactone and active metabolite.
This study was designed to get the direct evidence of the autoinduction metabolism for the antimalarial drug artemisinin (QHS). The sex effect on the pharmacokinetic profiles of QHS and its metabolites was also studied.
Two groups of rats received a single oral dose of QHS, and another two groups of rats were given oral doses of QHS once daily for 5 consecutive days. Plasma samples and its phase I and phase II metabolites were analysed for QHS, using a validated liquid chromatography tandem mass spectrometric (LC-MS) method.
Eight phase I metabolites (DQHS, M1–M7) and five phase II metabolites (M8–M12) of QHS were detected in rat plasma. The AUC0?t of the parent drug QHS, and its phase I metabolites DQHS, M2, M3 and M6 decreased significantly (p?<?0.05) with increased oral clearance (CL/F) (p?<?0.05) after 5-day oral doses of QHS to rats. There was no change (p?>?0.05) in AUC of M1 and M4, whereas its metabolites M5 and M7 exhibited higher AUC (p?<?0.05). The AUC of phase II metabolites M8, M11 and M12 also increased after multiple oral doses of QHS. Sex difference was observed for QHS and its metabolites DQHS, M1, M3, M5, M8 and M9 in rats after a single oral dose of QHS.
The results gave the direct evidence for the autoinduction of both phase I and phase II metabolism of QHS. The sex effect existed for QHS.
The aim of this investigation was to determine the pharmacokinetics and demethylation of caffeine (CF) and the metabolite/CF ratios that correlated best with CF clearance, which were used to evaluate hepatic drug-oxidizing capacity of CF after a single intravenous dose (5?mg/kg) in hair goats (n?=?9).
Pharmacokinetic parameters of CF and its metabolites, theobromine (TB), paraxanthine (PX) and theophylline (TP), were calculated. The plasma metabolic ratios TB/CF, PX/CF, TP/CF and TB+PX+TP/CF were determined at 6, 8 and 10?h after CF administration to evaluate their hepatic drug-oxidizing capacity.
The plasma concentration–time data of CF were fit to a two-compartment model in all animals. The clearance of CF was 0.08?±?0.02?L/h/kg, and the volume of distribution was 0.91?±?0.16?L/kg. The demethylation fractions of CF to TB, PX and TP were 0.24, 0.37 and 0.39, respectively.
Correlations between the metabolic ratios and CF clearance were quite high, except for the PX/CF ratio, particularly at 6?h (r?=?0.650–0.750, P?<?0.01, 0.05) and 10?h (r?=?0.650–0.767, P?<?0.01, 0.05).
Plasma metabolite/CF ratios, except for the PX/CF ratio, may be useful as an alternative to measurements of CF clearance for the determination of the hepatic drug-oxidizing capacity in goats.
We compared the intrinsic clearance (CLint) of a number of substrates in suspensions of fresh and cryopreserved human hepatocytes from seven donors.
CLint values for a cocktail incubation of phenacetin, diclofenac, diazepam, bufuralol, midazolam, and hydroxycoumarin were 4.9?±?3.4, 18?±?7.2, 5.1?±?4.9, 6.3?±?3.3, 9.8?±?5.8 and 22?±?14?μl min?1/106 cells, respectively, and they correlated well with corresponding CLint values using cryopreserved hepatocytes from 25 different donors.
CLint values of each cocktail substrate and 20 AstraZeneca new chemical entities were compared in fresh and cryopreserved hepatocytes from the same three donors. There was a statistically significant correlation between CLint in fresh and cryopreserved hepatocytes for each of the three livers (p?int values was 1.03.
In conclusion, the results add further support to the use of cryopreserved human hepatocytes as a screening model for the intrinsic clearance of new chemical entities.
This work aimed to investigate plasma pharmacokinetics and tissue distribution of a new acridine derivative 5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (AC04) and its 1-oxo-AC04 metabolite disposition in Wistar rats.
After a single AC04 1.5?mg/kg intravenous (i.v.) bolus dose, blood samples were taken up to 120?h. Plasma samples were deproteinization, and AC04 and metabolite were quantified by validated liquid chromatography in tandem with mass spectrometry method. Protein binding was determined by ultrafiltration. AC04 tissue disposition was evaluated after i.v. bolus dose.
Individual AC04 concentration–time profiles were best fitted by a two-compartment model showing CLtot of 3.4?±?3.4?L/h/kg, VdSS of 137.9?±?91.4?L/kg, AUC0–∞ of 788?±?483 ng·h/mL and a t1/2 of 45.5?±?31.5?h. Protein binding was 98.1?±?1.6%. AC04 showed higher penetration into the lung, spleen and liver, with AUC0–96 of 798,443, 263,211 and 303,722 ng·h/mL, respectively. The 1-oxo-AC04 metabolite represented 10% of AC04 plasma concentration, showing a t1/2 of 23.2?±?10.4?h.
These results suggest that, despite the small free plasma fraction, AC04 penetrates extensively reaching high concentrations in most tissues residing for a long time, which is important for its activity on solid tumours. All results combined indicate that AC04 is potentially a good antitumour candidate.