The multiple-dosing pharmacokinetics of artemether,artesunate, and their metabolite dihydroartemisinin in rats

1. 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.

2. 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.

3. ARM and ARS could be biotransformed to metabolite DHA almost immediately after oral administration to rats. The area under the plasma concentration–time curve (AUC_0–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 AUC_0–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.

4. 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.

     

Autoinduction of phase I and phase II metabolism of artemisinin in rats

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 AUC(0-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.     

Dose-independent pharmacokinetics of trimethadione and its metabolite in rats

The aim of the present study was to examine the dose-independent kinetics of trimethadione (1) and its only metabolite dimethadione, 5,5-dimethyl-2,4-oxazolidinedione (2), after oral administration of 1-, 2-, and 4-mg/kg doses of 1 to rats. Pharmacokinetic parameters determined after oral administration of these doses showed that the half-life (t 1/2), metabolic clearance (CL), and apparent volume of distribution (Vd) were not significantly changed by increasing or decreasing the dose of 1, whereas there was a linear relationship between the dose of 1 and the area under the curve (AUC) (1, r = 0.912; 2, r = 0.976) or the maximum serum concentration (Cmax) (1, r = 0.990; 2, r = 0.980). The ratios of 2 to 1 at 1 and 2 h after oral administration of 1 were not significantly different. These experiments indicate that serum pharmacokinetic behavior of 1 and 2 1 or 2 h after oral administration of 1 to the rat is independent of the dose of 1 in the 1-4 mg/kg range.     

Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159, a new erectogenic, to mice, rats, rabbits, dogs and humans

Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159 to mice, rats, rabbits, dogs and humans were investigated. After intravenous administration of DA-8159, the formation of DA-8164 decreased in the order mice, rats, rabbits and dogs; the AUC(DA-8164)/AUC(DA-8159) ratios were 0.479, 0.199, 0.0452 and close to 0 (DA-8164 was below the detection limit in dog plasma), respectively. After oral administration of DA-8159, the formation of DA-8164 was considerable in mice, rats and humans, but almost negligible in dogs; the AUC (or AUC(0-t))(DA-8164)/AUC (or AUC(0-t))(DA-8159) ratios were 2.99, 2.67, 1.39 and 0.0650, respectively. The above data suggested that the formation of DA-8164 was almost negligible after both intravenous and oral administration in dogs. The species differences for the formation of DA-8164 may be due to the involvement of different CYP isozymes for each species and/or a different amount or activity of CYP isozyme if the same CYP isozyme is involved for the formation of DA-8164 for all species. The AUC (or AUC(0-t))(DA-8164)/AUC (or AUC(0-t))(DA-8159) ratios after oral administration were greater than those after intravenous administration in mice, rats and dogs, and this could be due to considerable first-pass (gastric, intestinal and/or hepatic) effects in the species as proved in rats.     

盐酸阿比朵尔在大鼠体内的药代动力学

目的研究盐酸阿比朵尔在大鼠体内的药代动力学。方法将健康♂Wistar系大鼠(200～220 g),随机分组,每组6只。单次灌胃给予药物,剂量分别为9、18、54 mg.kg-1,从眼眶静脉丛分时取血、处理。采用高效液相色谱-质谱联用方法测定药物在血浆中的浓度,应用DAS 2.0软件计算主要药代动力学参数。结果按9、18、54 mg.kg-13个剂量分别单次灌胃给予大鼠盐酸阿比朵尔后,药物在动物体内的Cmax分别为644.1、1002、4711μg.L-1;Tmax分别为0.35、0.28、0.18 h;AUC0-t分别为1127、1956、6790μg.h.L-1;AUC0-∞分别为1250、2224、7558μg.h.L-1;T12分别为3.2、3.6、3.3 h。结论以上数据经统计学分析,结果表明:在9～54 mg.kg-1剂量范围内,单剂量灌胃给予大鼠盐酸阿比朵尔后,药物在动物体内的动力学行为具有线性特征。     

Pharmacokinetic difference between S-（＋）- and R-（-）-etodolac in rats

AIM: To study whether etodolac enantiomers have pharmacokinetic difference after oral administration. METHODS: Fourteen rats, divided into two groups randomly, were orally given S-( )- or R-(-)-etodolac at a single dose of 20 mg/kg, respectively. Blood samples were collected before and at 5, 10, 20, 30 min and 1, 3, 6, 12, 24, 48, 72 h after treatment. The plasma samples were analyzed with a high-performance liquid chromatographic method. RESULTS: The calibration curves were linear in the range of 0.5-50.0 mg/L (r=0.9999) to S-( )-etodolac and 2.0-200.0 mg/L (r=0.9999) to R-(-)-etodolac, respectively. The main pharmacokinetic parameters of S-( )- and R-(-)-etodolac were as follows: t1/2(λz)18±4 h vs 19.4±2.2 h, tmax 3.3±2.6 h vs 4±4 h; Cmax 29±6 mg/L vs97±14 mg/L, AUC0-t 706±100 h·mg·L-1 vs 2940±400 h·mg·L-1, CL(s) 0.030±0.006 L·kg-1·h-1 vs 0.0065±0.0010 L·kg-1·h-1 and V/F 0.25±0.22 L·kg-1 vs 0.03±0.05 L·kg-1. There was no significant difference in t1/2(λz) and tmax between S-( )-     

Effects of poloxamer 407-induced hyperlipidemia on the pharmacokinetics of carbamazepine and its 10,11-epoxide metabolite in rats: Impact of decreased expression of both CYP3A1/2 and microsomal epoxide hydrolase

The pharmacokinetics of carbamazepine (CBZ) and its active 10,11-epoxide metabolite (CBZ-E) were evaluated after intravenous and oral administration of 5 mg/kg CBZ to rats with hyperlipidemia induced by poloxamer 407 (HL rats) and controls. The total area under the plasma concentration-time curve (AUC) of CBZ in HL rats after intravenous administration was significantly greater than that in controls due to their slower non-renal clearance (CL(NR)). This was due to slower hepatic CL(int) for metabolism of CBZ to CBZ-E in HL rats via CYP3A1/2. This result was consistent with a previous study indicating reduced hepatic CYP3A1/2 expression in HL rats. Interestingly, the AUC of CBZ-E was also increased in HL rats, while AUC(CBZ-E)/AUC(CBZ) ratios remained unchanged. These results suggested that further metabolism of CBZ-E to the inactive metabolite trans-10,11-dihydoxyl-10,11-dihydro-CBZ (CBZ-D) via microsomal epoxide hydrolase (mEH) was also slowed in HL rats. The significantly reduced hepatic mRNA level and expression of mEH protein in HL rats compared to controls confirmed the above hypothesis. Similar pharmacokinetic changes were observed in HL rats after oral administration of CBZ. These findings have potential therapeutic implications assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Caution is required regarding pharmacotherapy in the hyperlipidemic state in cases where drugs that are metabolized principally by CYP3A1/2 or mEH and have a narrow therapeutic range are in use.     

Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers

Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism. In an open, two-phase crossover study, seven healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone, or 500 mg mefloquine plus a long-term administration of 600 mg rifampin. Blood samples were collected at specific time points over a 56-day period. Plasma mefloquine and its carboxylic acid metabolite were measured by HPLC for pharmacokinetic analysis. The results indicate that rifampin significantly decreased the area under the plasma concentration-time curve (AUC0 - infinity) of mefloquine by 68% (P < 0.01), maximum plasma concentration (Cmax) by 19% (P < 0.001), and elimination half-life (t1/2) by 63% (P < 0.01), whereas the time to reach Cmax (t(max)) of mefloquine was unaffected. The apparent oral clearance (CL) of mefloquine was significantly increased by 281% (P < 0.01). After administration of rifampin, the Cmax of the carboxylic acid metabolite of mefloquine was significantly increased by 47% (P < 0.05), whereas the t1/2 was significantly decreased by 39% (P < 0.01), and t(max) by 76% (P < 0.01). The AUC0 - infinity and CL of the mefloquine metabolite were increased by 30% and 25%, respectively, but were not significantly different from the control phase. The results indicate that rifampin reduces the plasma concentration of a single oral dose of 500 mg mefloquine by increasing metabolism of mefloquine in the liver and gut wall. The CYP3A4 isozyme most likely plays an important role in the enhanced metabolism of mefloquine. Simultaneous use of rifampin and mefloquine should be avoided to optimize the therapeutic efficacy of mefloquine and prevent the risk of Plasmodium falciparum resistance in malarial treatment.     

Effect of coenzyme Q10 on the disposition of doxorubicin in rats.

The effect of exogenous coenzyme Q10 (CoQ10) on the pharmacokinetic profiles and biliary excretion of doxorubicin and its main metabolites, doxorubicinol and doxorubicinolone, was investigated in rats. No statistically significant changes in the pharmacokinetic parameters of doxorubicin was observed following the intravenous bolus administration of 10 mg/kg doxorubicin to rats during a 6-day oral regimen of CoQ10 (20 mg/kg daily). Treatment with CoQ10 did not affect the formation of the doxorubicinol, but produced a 75% increase (P < 0.05) in the AUC of doxorubicinolone. Correspondingly, CoQ10 had no apparent effect on the biliary excretion of doxorubicin and formation clearance of doxorubicinol, whereas the formation clearance of doxorubicinolone was significantly increased by 69% in CoQ10-pretreated rats (P < 0.05). Overall, the results suggest that CoQ10 treatment has no significant effect on the pharmacokinetics of doxorubicin and the formation of the cytotoxic metabolite, doxorubicinol.     

反义寡核苷酸药物癌泰得及其代谢产物的猕猴体内药代动力学研究

研究反义寡核苷酸药物癌泰得(cantide)及其代谢产物在猕猴体内的药代动力学特征。通过采用两步固相萃取法结合无胶筛分毛细管电泳技术测定猕猴血浆中的癌泰得及其代谢产物的血药浓度,并计算药代动力学参数。研究比较了猕猴单次静脉滴注不同剂量(8,16,24 mg.kg-1)癌泰得后血浆中原形药物及其代谢产物M1和M2的药代动力学行为。猕猴经静脉滴注给药后,癌泰得在血浆中消除迅速,末端t1/2为57.91～77.97 min,其Cmax、AUC0-inf和AUC0-t与给药剂量的线性相关系数(r)分别为0.991 8、0.956 8和0.977 3。代谢产物紧随原形药物之后达到峰浓度,且峰浓度均明显低于原形药物。原形药物及其代谢产物M1和M2的CLs分别为1.60～2.19、5.92～8.58和6.07～8.78 mL.min-1.kg-1。结果表明癌泰得原形及其代谢产物的Cmax、AUC0-inf和AUC0-t均随给药剂量增加而增加。代谢产物的清除率大于原形药物,且代谢产物在高剂量组表现为MRT明显延长,末端消除相半衰期亦增大。     

Effect of pioglitazone on the pharmacokinetics of verapamil and its major metabolite,norverapamil, in rats

Pioglitazone, a thiazolidinedione antidiabetic drug, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. This study investigated the effect of pioglitazone on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats, after oral administration of verapamil (9 mg/kg) in the presence or absence of pioglitazone (0.3 or 1.0 mg/kg). Pioglitazone altered verapamil pharmacokinetics compared with verapamil alone. The presence of 1.0 mg/kg of pioglitazone significantly (p < 0.05) increased the area under the plasma concentration-time curve (AUC) and the peak concentration (C(max)) of verapamil by 49.0% and 46.8%, respectively, and significantly (p < 0.05) decreased the total plasma clearance (CL/F) of verapamil by 32.8%. The metabolite-parent AUC ratio in the presence of pioglitazone (1.0 mg/kg) significantly (p < 0.05) decreased by 21.9% compared to the control group. Thus, coadministration of pioglitazone inhibited the CYP3A4-mediated metabolism of verapamil.     

Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol intake in rats

Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV-infected patients, it was found that plasma concentrations of saquinavir (SQV) were reduced in patients who had a habit of alcohol intake during double protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake in rats. After oral administration of SQV alone (20 mg/kg) in rats prepared by free access to 15% ethanol solution for 14 days (day 14 rats), the area under the concentration vs time curves (AUC) showed a significant decrease (p<0.01) in comparison with control rats from 0.78+/-0.10 to 0.38+/-0.03 microg h/ml. For intravenous administration of SQV alone (5 mg/kg) to day 14 rats, the total body clearance increased significantly by 1.4-fold (p<0.05), whereas for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found between control and day 14 rats. With RTV, which has the strongest inhibitory effect on the CYP3A enzyme of the current HIV protease inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg in day 14 rats also decreased significantly (p<0.01) from 1.30+/-0.06 to 0.57+/-0.05 microg h/ml and from 17.63+/-1.66 to 4.18+/-0.94 microg h/ml, respectively, indicating that the degree of the decrease of AUC values after oral administration with RTV after ethanol intake was larger than the mono-therapy with SQV. This study showed that ethanol-intake decreases the bioavailability of SQV after oral administration alone or with RTV. These observations provide useful information for the treatment of HIV-infected patients when they receive a combination therapy with SQV and RTV, and arouse attention for the effects of alcohol intake.     

Influence of cholestyramine on the pharmacokinetics of rosiglitazone and its metabolite, desmethylrosiglitazone, after oral and intravenous dosing of rosiglitazone: impact on oral bioavailability, absorption, and metabolic disposition in rats

The possible influence of the bile acid-sequestering agent cholestyramine (CSA), which is a basic co-medication in hypercholesterolemic patients, on the pharmacokinetics of rosiglitazone (RGL) and its circulating metabolite desmethylrosiglitazone (DMRGL) was investigated following a single oral and intravenous dose of RGL to Wistar rats. The pharmacokinetic parameters of RGL and DMRGL were evaluated following oral or intravenous administration of RGL to rats at 10 mg kg-1 with and without pre-treatment (0.5 h before RGL administration) of CSA at 0.057, 0.115, 0.23 and 0.34 g kg-1 doses. With an increase in CSA dose there was dose-dependent decrease in area under the curve (AUC)(0-infinity) and Cmax with no change in Tmax, Kel and t1/2 values for both RGL and DMRGL following oral administration of RGL. The oral bioavailability of RGL was reduced by 19.9, 35.6, 53.8 and 72.0% in rats following pre-treatment with CSA at 0.057, 0.115, 0.230 and 0.340 g kg-1, respectively. There was no change in the above-mentioned pharmacokinetic parameters for RGL and DMRGL in rats when RGL was given intravenously following pre-treatment with the above-mentioned oral doses of CSA. Another objective of the study was to determine the effect of staggered oral CSA dosing at 1, 2 and 4 h after oral RGL administration at 10 mg kg-1. AUC(0-infinity) of RGL and DMRGL was reduced following CSA staggered administration at 1 h, whereas 2- and 4-h staggered dose administration of CSA had no effect on the AUC(0-infinity) of RGL and DMRGL. Irrespective of CSA staggered dose administration there was no change in other pharmacokinetic parameters, namely Cmax, Tmax, Kel and t1/2. The apparent formation rate constant (Kf) of DMRGL was also calculated to show that only the absorption of RGL was affected, not the apparent formation rate of DMRGL. The authors also studied the in vitro adsorption of RGL (100, 250, 500 microg ml-1) at various pH conditions (pH 2, 4 and 7) and different concentrations of CSA (15, 30, 60 and 120 mg ml-1). The percentage binding of CSA was in the range 50-72% (at pH 2), 74-89% (at pH 4) and 97-100% (at pH 7). In conclusion, we carried out a systematic investigation demonstrating mechanistically the interaction potential of RGL when co-administered with CSA. The applicability of the metabolite data after intravenous and oral dosing and pH-based binding experiments further adds credence to the key findings.     

Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat

The pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have been investigated in Wistar rats after 10 mgkg(-1) deramciclane fumarate was administered orally, intraperitoneally or intravenously. A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction technique was used to determine plasma levels of the parent compound and its N-desmethyl metabolite. After oral administration the absorption of the parent compound was very fast (t(max) 0.5h). The maximum plasma concentration (C(max)) was detected at 44.9, > or =177.8 and > or =2643.0 ngmL(-1) after oral, intraperitoneal and intravenous administration of deramciclane, respectively. For the metabolite the respective Cmax values were 32.0, > or =25.4 and 51.0 ngmL(-1). The pharmacokinetic curves of both the parent compound and its metabolite showed enterohepatic recirculation for all administration routes. The biological half-life (tbeta 1/2) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmethyl metabolite the range was 2.90-5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC0-infinity, of deramciclane was 29.2- and 5.4-times higher than that observed after oral and intraperitoneal treatment, respectively. These AUC0-infinity ratios were only 2.1- and 1.5-times higher for the metabolite. The absolute bioavailability of deramciclane in rats was 3.42% after oral and 18.49% after intraperitoneal administration. The comparative pharmacokinetic study of deramciclane in rat after the different administration routes showed fast absorption. Furthermore, plasma levels were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass metabolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.     

Effects of bacterial lipopolysaccharide on the pharmacokinetics of metformin in rats

It was reported that the hepatic microsomal cytochrome P450 (CYP) 2C11, 2D1, and 3A1 (not via the CYP1A2, 2B1/2, and 2E1) were involved in the metabolism of metformin in rats. It was also reported that the expressions of CYP2C11 and 3A2 decreased in rats pretreated with Klebsiella pneumoniae lipopolysaccharide (KPLPS). Therefore, the pharmacokinetic parameters of metformin could be changed in rats pretreated with KPLPS. Hence, the pharmacokinetic parameters of metformin were compared after both intravenous and oral administration of the drug at a dose of 100mg/kg to control rats and rats pretreated with KPLPS. After intravenous administration of metformin to rats pretreated with KPLPS, the total area under the plasma concentration-time curve from time 0 to infinity (AUC) of the drug was significantly greater (40.5% increase) than the controls due to significantly smaller CL value (27.7% decrease) than the controls. The significantly smaller CL value could be due to significantly smaller both the CL(R) and CL(NR) values (34.0% and 18.1% decrease, respectively) than the controls. The significantly smaller CL(NR) value could be due to decrease in the expressions of CYP2C11 and 3A2 in rats pretreated with KPLPS. After oral administration of metformin, the AUC of the drug was not significantly different between two groups of rats, and this may be at least partly due to decrease in absorption from the gastrointestinal tract compared with the controls.     

Pharmacokinetics of chlorambucil in patients with chronic lymphocytic leukaemia: comparison of different days, cycles and doses

The effects of repeated treatment cycles and different doses on intraindividual variation in oral bioavailability of chlorambucil and its first, active, and more toxic metabolite, phenylacetic acid mustard, were studied. Chlorambucil and phenylacetic acid mustard concentrations were measured with HPLC on Day 1 and on Day 4 in 15 timed blood samples from 11 chronic lymphocytic leukaemia patients receiving chlorambucil therapy cycles. Bioavailability was evaluated also after the first chlorambucil doses of six consecutive treatment cycles repeated every 4 weeks with increasing chlorambucil doses starting with 0.8 mg/kg/4 days, and increased by 0.1 mg/kg/4 days cycle. Area under the concentration-time-curve (AUC) from t=0 to infinite was in average 3.2 hr* microg/ml for the first cycle, and decreased by 17% in four days (P<0.05). The mean distribution half-life of chlorambucil was 0.49 hr and the terminal elimination half-life 2.45 hr. The bioavailability of chlorambucil decreased further when 4-day treatment cycles were repeated. For the fifth cycle, dose-corrected AUC for the first 2 hr was 33% smaller than that for the first cycle (P for trend <0.01). Data suggest accelerated metabolism and elimination of chlorambucil and phenylacetic acid mustard, but reduced oral bioavailability of chlorambucil cannot be excluded. However, except for AUC, none of the pharmacokinetic parameters of chlorambucil changed significantly during the first 4-day treatment period. The maximal plasma concentration and AUC of phenylacetic acid mustard did not change significantly during repeated treatment cycles. According to this trial a dose adjustment of chlorambucil is not necessary during a short-term course, but may be necessary when treatment cycles are repeated. An average increase in the chlorambucil dose of 10% per cycle maintains similar plasma concentration of chlorambucil.     

Pharmacokinetic study of the novel, synthetic trioxane antimalarial compound 97-78 in rats using an LC-MS/MS method for quantification

The present study has been designed to investigate the pharmacokinetic parameters of the novel trioxane antimalarial 97-78 (US Patent 6316493 B1, 2001) in male and female rats after single oral and intravenous administration. The pharmacokinetic profile of 97-78 was investigated in the form of its completely converted metabolite 97-63 after dose administration. Quantification of metabolite 97-63 in rat plasma was achieved using a simple and rapid LC-MS/MS method. The LC-MS/MS method has been validated in terms of accuracy, precision, sensitivity and recovery for metabolite 97-63 in rat plasma. The intra- and interday accuracy (% bias) and precision (% RSD) values of the assay were less than 10% for metabolite 97-63. The chromatographic run time was 4.0 min and the weighted (1/x2) calibration curves were linear over the range 1.56-200 ng/ml. This method was successfully applied for analysis of pharmacokinetic study samples. Maximum plasma concentrations of 97-63 at 47 mg/kg oral administration in male and female rats were 1986.6 ng/ml and 4086.7 ng/ml at time (Tmax) 0.92 h and 0.58 h, respectively. The area under the curve (AUC(0-infinity)), elimination half-life (t(1/2) beta) and mean residence time (MRT) were 4669.98 ng x h/ml, 2.8 h and 4.2 h in male and 11786.0 ng x h/ml, 4.52 h and 4.32 h in female rats respectively. After single oral and intravenous administration of 97-78 to male and female rats significant differences were observed in pharmacokinetic parameters (AUC and t (1/2) beta) for metabolite 97-63.     

人参皂苷Rg_l及其代谢产物的药代动力学研究

研究静注和灌胃给予一定量人参皂苷Rg1后,其原形和3种代谢产物的药代动力学。以Wistar大鼠为模型动物,以LC-MS/MS法测定血浆中人参皂苷Rg1及其代谢产物的浓度,并计算药代动力学参数。灌胃给药后,在血浆中检测到人参皂苷Rg1、Rh1、F1和原人参三醇4种物质。其Tmax分别为0.92、3.64、5.17和7.30h,MRT分别为2.68、5.06、6.65和5.33h,AUC0-t为2363.5、4185.5、3774.3和396.2ng·mL-1·h。静注给药后,在血浆中检测到人参皂苷Rg1、Rh1和F13种物质。其T1/2β分别为3.12、5.87和6.87h,MRT分别为1.92、5.99和7.13h,AUC0-t分别为1454.7、597.5和805.6ng·mL-1·h。结果表明灌胃给药后,大鼠体内的人参皂苷Rg1代谢产物的量超过原形药,且代谢产物的吸收和消除速率相对缓慢。静注给药后,大鼠体内的人参皂苷Rg1以原形为主,但仍有少量代谢产物存在,且代谢产物的吸收和消除速率相对缓慢。     

Pharmacokinetics of oral artesunate in thai patients with uncomplicated falciparum malaria

The pharmacokinetics of artesunate and its major plasma metabolite, dihydroartemisinin, were investigated in 11 Thai male patients with acute uncomplicated falciparum malaria during the acute and recovery phases. Patients were given an oral dose of 200mg artesunate (Guilin Pharmaceutical) on the first day, followed by 100mg 12 hours later, then 100mg daily for another 4 days (total dose of 700mg). All the patients showed a rapid initial response with median (range) parasite and fever clearance times of 30 (18 to 60) and 24 (4 to 94) hours, respectively; no patients showed reappearance of parasites during the 28-day follow-up period. No significant clinical adverse effects were detected in any patient. Acute phase malaria infection significantly influenced the pharmacokinetics of artesunate and its active metabolite, dihydroartemisinin. Maximum plasma drug concentration (C(max)), absorption half-life (t((1/2)a)), area under the plasma concentration-time curve from zero to the last observed time (AUC) and terminal elimination half-life (t((1/2)z)) of artesunate were decreased, while apparent total body clearance (CL/f) was increased during the acute phase, compared with the recovery phase. In addition, a decrease in the C(max) and an increase in the AUC(DHA/ARS ) ratio were found. Optimisation of therapy with oral artesunate should therefore be based on the kinetics of the drug and dihydroartemisinin in malaria patients with acute phase infection.     

Pharmacokinetic studies of a novel anticonvulsant, 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane, in rats.

The pharmacokinetic properties of 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane (AAP-Cl) were studied in rats after intravenous and oral administration. The blood concentrations of AAP-Cl in rats showed a biexponential decline following intravenous administration of pharmacologic doses ranging from 10 to 100 mg/kg in rats. The terminal elimination half-lives (t((1/2)beta)) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 5.80+/-0.30, 6.02+/-0.16 and 6.05+/-0.08 h, respectively. The total clearances (CL) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 1.29+/-1.10, 1.38+/-0.07 and 1.33+/-0.13l/(h kg), respectively. The apparent volumes of distribution at steady state (V(ss)) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 7.96+/-0.51, 8.24+/-0.31 and 8.17+/-0.43l/kg, respectively. The AUC(0-infinity) increased proportionately to the intravenous bolus dose of AAP-Cl given (10-100 mg/kg). Statistical analysis of the t((1/2)beta), V(ss) and CL values for AAP-Cl between doses indicates that AAP-Cl exhibits dose-independent kinetics (P>0.05). AAP-Cl was absorbed rapidly after an oral dose of 100 mg/kg with peak concentrations (C(max)) in blood (3.5+/-0.33 microg/ml) reached after 30 min of drug administration. The oral bioavailability of AAP-Cl was 19.5+/-3.4% following administration of a single 100 mg/kg dose in rats. Urine analysis indicates that 2.5+/-0.45% of the administered dose of AAP-Cl (100 mg/kg, p.o.) is recovered unchanged in urine within 0-24 h. These findings may be useful in designing new aminoalkylpyridine anticonvulsants with improved efficacy and disposition profiles in animal models of epilepsy.