Effect of injection routes on pharmacokinetics and lactone/carboxylate equilibrium of 9-Nitrocamptothecin in rats

Pharmacokinetics and lactone/carboxylate equilibrium of 9-Nitrocamptothecin (9-NC) were compared after intravenous (i.v.) and intramuscular (i.m.) injection at a dose of 1.5 mg/kg 9-NC solution. The concentrations of three different forms of 9-NC, namely lactone, carboxylate and total 9-NC, were measured by HPLC analysis. Injection routes were demonstrated to have significant effect on pharmacokinetics of 9-NC. Compared with i.v. injection route, mean residence time (MRT) of 9-NC three forms was significantly prolonged following i.m. route (p < 0.05). The AUC_0–∞ ratios of i.m. to i.v. route were calculated to be 102 ± 43%, 273 ± 221% and 150 ± 62% for lactone, carboxylate and total 9-NC, respectively. Compared with i.v. injection route, although AUC_0–∞ was barely changed, MRT of lactone 9-NC was dramatically prolonged 4.5-fold after i.m. injection, which may account for the reported improved antitumor efficacy. However, the results of the present study also demonstrated that i.m. injection route increased both AUC_0–∞ and MRT of carboxylate 9-NC more significantly. Since the carboxylate form of CPT analogs including 9-NC is associated with their unwanted toxicity, i.m. injection route might lead to severe toxicity compared with i.v. route. Lactone/carboxylate equilibrium was also significantly influenced by injection routes. Based on the AUC_0–∞ measurements, the lactone 9-NC constituted 50 ± 8% and 32 ± 7% of circulating total 9-NC after i.v. or i.m. administration, respectively (p < 0.01).     

不同内酯型比例9-硝基喜树碱对胆汁排泄的影响

目的考察9-硝基喜树碱(9-nitrocamptothecin,9-NC)不同形式(内酯型或羧酸盐型)给药对胆汁排泄的影响。方法建立HPLC测定胆汁中9-NC浓度的方法,比较不同内酯型比例的9-NC溶液以4 mg·kg?1剂量静脉注射后大鼠胆汁中原形药物的排泄量。结果静脉注射100%,75%,50%,25%,0%内酯型比例的9-NC在8 h内的胆汁累积排泄百分数分别为(7.03±2.23)%,(13.36±0.83)%,(22.68±4.83)%,(28.01±6.71)%,(32.65±2.82)%。结论 9-NC羧酸盐型更易经胆汁途径排泄。     

9-nitrocamptothecin polymeric nanoparticles: cytotoxicity and pharmacokinetic studies of lactone and total forms of drug in rats

The objective of this study was to evaluate the cytotoxicity and pharmacokinetics of total and lactone forms of 9-nitrocamptothecin (9-NC), an effective antineoplastic drug, after intravenous injection of drug incorporated into poly (DL-lactic-glycolic acid) nanoparticles (NPs). Drug-loaded NPs (9-NC.NP) were prepared by the nanoprecipitation method and examined for particle characteristics and in-vitro release in phosphate buffered saline. The best formulation showed a narrow size with an average diameter of 207+/-26 nm and a drug loading of more than 33.5%. The drug release profile showed a sustained 9-NC release up to 160 h. For a pharmacokinetic study, the concentration of 9-NC as the lactone form (9-NC.lac) and as the total of the lactone and carboxylate forms (9-NC.tot) in plasma was determined by using reverse-phase high performance liquid chromatography after intravenous administration of 9-NC.NP and a control solution to cannulated Wistar rats. In-vitro cytotoxic activity of 9-NC.NP and control solution was evaluated on the human ovarian cancer cell line (A2780sn) by MTT cell cytotoxicity assay. Results of in-vivo studies showed that NP encapsulation markedly increased the plasma concentration of both lactone and total forms of 9-NC compared with free drug. In comparison with free drug, NPs resulted in 3.63-fold and 5.40-fold increases in area under the plasma concentration-versus-time curve (AUC(0-infinity)) for lactone and total forms of 9-NC, respectively. The values of mean residence time and elimination half-life (T(1/2)) were also significantly higher for NPs than for free drug. The in-vitro cytotoxicity study revealed that the IC50 value of NPs decreased 10-fold compared with the drug solution. Prepared NPs described here were considered potentially useful in both stabilizing and delivering 9-NC and enhancing the efficacy of this drug for cancer treatment for which high drug retention in the body, protection from the drug-active lactone form, and gradual drug release appeared to be related.     

9-硝基喜树碱在大鼠组织中的分布及内酯稳定性

考察9-硝基喜树碱(9-NC)静脉注射后在人鼠组织中的分布及内酯稳定性.建立了HPLC法间时测定组织和血浆中9-NC内酯浓度和总浓度.大鼠静脉注射9-NC溶液后测定各时间点组织中内酯浓度、总浓度和内酯比例.大多数组织中的9-NC内酯比例明显高于血浆;肝中的内酯比例最低,甚至低于血浆;血浆、肾和小肠中的内酯比例随时问延长而下降.9-NC在肝以外的组织中内酯稳定性显著优于血浆.     

9-硝基20（S）喜树碱在大鼠体内的药物动力学

目的:研究9-硝基喜树碱在大鼠体内的药物动力学及排泄。方法:利用高效液相色谱法对静脉注射或灌胃给药后的大鼠血浆及排泄物样品进行分析。绘制血浆药物浓度-时间曲线,并进行非室模型分析及房室模型拟合。利用线性回归评价药物浓度-时间曲线下面积(AUC)与剂量之间、血浆药物峰浓度(C_(max))与剂量之间的线性关系;不同剂量下的药物半衰期及清除率通过方差分析进行比较。计算原形药物自大鼠体内的排泄量。结果:大鼠分别以1.5、3、6mg/kg静脉给药后,AUC_(o-t)分别为633、1606和3011h·μg·L~(-1);t_(1/2)分别为0.5、0.5和0.7h;大鼠分别以3、6、12mg/kg灌胃给药后,C_(max)分别为203、417和1150μg/L,T_(max)均在0.3h左右,AUC_(o-t)分别为269、439和881h·μg·L~(-1);t1/2分别为1.7、0.9和0.9h。9-硝基喜树碱在大鼠体内的绝对生物利用度为14.6％,这与灌胃及静脉注射两种给药途径下原形药物(胆汁和尿中)累积排泄量之比值相一致。结论:9-硝基喜树碱在大鼠体内动力学过程符合二室模型。静脉给药后,药物在大鼠体内的动力学不依赖于剂量,肾排泄为原形药物的主要排泄途径;灌胃给药后,药物绝对生物利用度低,原形药物大部分经粪排泄。     

Pharmacokinetics and excretion of hydroxysafflor yellow A, a potent neuroprotective agent from safflower, in rats and dogs

Studies were conducted to characterize the pharmacokinetics and excretion of hydroxysafflor yellow A (HSYA) in rats and dogs after administration by intravenous injection or infusion. Plasma, urine, feces and bile concentrations of HSYA were measured using five validated mild HPLC methods. Linear pharmacokinetics of HSYA after the intravenous administrations were found at doses ranging from 3 to 24 mg/kg in rats and from 6 to 24 mg/kg in dogs. At a dose of 3 mg/kg, HSYA in urine, feces and bile was determined. For 48 h after dosing, the amount of urinary excretion accounted for 52.6 +/- 17.9 % (range: 31.1 - 78.7%, n = 6) of the dose, and the amount of fecal amount accounted for 8.4 +/- 5.3% (range 1.7 - 16.4%, n = 6) of the dose. Biliary excretion amount accounted for 1.4 +/- 1.0% (range 0.4-2.9%; n = 6) of the dose for 24 h after dosing. Percent plasma protein binding of HSYA ranged from 48.0 to 54.6% at 72 h. In summary, five mild HPLC methods for the determinations of HSYA in rat plasma, urine, feces, bile and dog plasma have been developed and successfully applied to preclinical pharmacokinetics and excretion of HSYA in rats and dogs. The results of excretion studies indicated that HSYA was rapidly excreted as unchanged drug in the urine. In view of previous pharmacological work, the concentration-dependent neuroprotective effect of HSYA in rats was defined.     

The disposition and pharmacokinetics of ketoconazole in the rat

The disposition, biliary excretion, and pharmacokinetics of ketoconazole in Sprague-Dawley rats were determined after intravenous administration. Greater than 80% of the radioactivity after a 5 mg/kg iv dose of 3H-ketoconazole was excreted in the feces. Urinary excretion was essentially complete after 48 hr; however, fecal excretion was prolonged over a 7-day period. Biliary excretion of radioactivity averaged 54.3 +/- 18.0% of the dose over a 7.5-8-hr period in pentobarbital-anesthesized rats. The possibility of enterohepatic recirculation was examined using a linked rat technique. Less than 2% of the radioactivity was found in the recipient bile over 9-12 hr. In eight male rats, the plasma pharmacokinetics of ketoconazole, as determined by an HPLC assay with fluorescence detection, were as follows: VD = 655 +/- 91 ml/kg, Cl = 14.4 +/- 5.1 ml/min/kg, and t 1/2 = 35.0 +/- 12.3 min. Three of the rats were given an additional oral dose to determine absolute bioavailability. The time to peak was 30-60 min, and the bioavailability was 35.8 +/- 3.55%. Previous studies have indicated that ketoconazole is well absorbed in rats; therefore, the poor bioavailability is probably due to first pass metabolism. The prolonged fecal excretion of radioactivity from an intravenous dose was probably caused by slow elimination of ketoconazole metabolites.     

The pharmacokinetics of aspirin in rats and the effect of buffer

Aspirin (acetylsalicyclic acid) was administered to rats intravenously, orally, and intraintestinally at different doses or in different dosage forms. The distribution and elimination kinetics of aspirin in rats following intravenous administration were best described by a two-compartmental open system and were dose independent up to 15 mg/kg. The terminal elimination half-life following intravenous dosing (10 mg/kg) was 3.36 +/- 0.85 min (n = 15) with the clearance being 8.40 +/- 1.24 L/(kg.hr). Intravenous distribution and elimination kinetics of aspirin in rats were not influenced by an orally administered buffered solution with a buffer capacity of 0.933 mEq ANC (acid neutralizing capacity) per kg of body weight. However, this orally buffered solution did change the gastrointestinal absorption kinetics of aspirin in rats. The absolute bioavailable dose of aspirin was 56.6 +/- 10.4% (n = 6) following its administration in an unbuffered solution while it was only 31.8 +/- 8.0% (n = 6) following administration in the buffered solution. The corresponding values of the absolute bioavailable doses were 43.4 +/- 3.7% and 25.5 +/- 1.8% following intraintestinal administration. The lower systemic availability of aspirin in the presence of buffer is attributed to a greater fraction of the administered dose becoming available for absorption from the intestine where the extraction efficiency is higher than that in the stomach.     

Metabolism and pharmacokinetics of S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine in rats

The metabolism and pharmacokinetics of a mixed disulfide S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine (AC-DDTC) were studied in rats. Two metabolites of AC-DDTC following i.v. and p.o. administration were identified in plasma and liver by HPLC and GC, namely N,N-diethyldithiocarbamate (DDTC) and the methyl ester of DDTC (Me-DDTC). AC-DDTC was very unstable in vivo and could not be detected neither in plasma nor in urine. Pharmacokinetic parameters of DDTC following intravenous administration of AC-DDTC (20 mg/kg) were calculated. DDTC has a low affinity to rat tissue and the total body clearance was 9.0 +/- 3.4 ml/min/kg. The mean residence time (MRT) was 111.5 +/- 16.3 min. After oral administration of 20 mg/kg AC-DDTC, maximal plasma concentration (Cmax) was 3.8 +/- 0.2 nmol/ml and the bioavailability was 7.04%. Cmax for DDTC at a dose of 120 mg/kg AC-DDTC was 40.1 +/- 2.2 nmol/ml. MRT was 47.1 +/- 2.8 min at a dose of 20 mg/kg and 110.5 +/- 6.0 min at 120 mg/kg.     

吐温80对9-硝基喜树碱脂质体药物动力学性质的影响

目的:考察吐温80对9-硝基喜树碱(9-NC)脂质体体内药物动力学以及内酯型/羧酸盐型平衡的影响。方法:采用薄膜法制备9-NC脂质体以及吐温80修饰的9-NC脂质体;12只大鼠随机分为两组,按1.5 mg.kg-1剂量分别给予9-NC普通脂质体和吐温80修饰的脂质体,于不同时间点取血,处理后测定9-NC内酯型浓度和总浓度(内酯/羧酸盐)。采用统计矩模型利用3P97程序计算药物动力学参数。结果:采用表面活性剂吐温80进行修饰后,9-NC内酯型和总浓度的AUC分别提高了1.47倍和1.65倍,内酯型和总浓度的清除率CL和表观分布容积Vss显著下降(P<0.01)。此外,总浓度的MRT以及t1/2延长(P<0.05)。结论:吐温80修饰使得9-NC内酯型比例有所下降,但没有显著性差异,9-NC吐温修饰对9-NC脂质体具有一定的长循环效果。     

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.     

HPLC法测定人血浆中9-硝基喜树碱内酯型浓度和总浓度

目的:建立以高效液相色谱法测定人血浆中9-硝基喜树碱内酯型浓度和总浓度的方法。方法:血浆样品采用—20℃甲醇快速沉淀蛋白后进行测定,其中色谱柱为shim-packCLS-ODS,流动相为甲醇∶1%三乙胺(冰醋酸调pH6.5)=55∶45,流速为1.0mL·min-1,检测波长370nm,进样量为50μL,柱温为40℃。测定总浓度的样品采用冰醋酸酸化上清液。并以该法测定了不同时间点离体人血浆中9-硝基喜树碱内酯型、羧酸盐型浓度和总浓度的变化。结果:9-硝基喜树碱血药浓度在0.10～10.0μg·mL-1范围内线性关系良好(r=0.9991),定量下限为0.10μg·mL-1,平均方法回收率、酸化回收率各为101.02%、101.46%。结论:本法操作简便、快速,适用于9-硝基喜树碱内酯结构稳定性的研究。     

Dose-independent pharmacokinetics of ondansetron in rats: contribution of hepatic and intestinal first-pass effects to low bioavailability

The pharmacokinetic parameters of ondansetron were evaluated after its intravenous (at doses of 1, 4, 8 and 20 mg/kg) and oral (4, 8 and 20 mg/kg) administration to rats. The gastric, intestinal and hepatic first-pass effects of ondansetron were also evaluated after its intravenous, oral, intraportal, intragastric and intraduodenal administration at a dose of 8 mg/kg to rats. After intravenous and oral administration of ondansetron, the drug exhibits dose-independent pharmacokinetics in rats. After oral administration of ondansetron at a dose of 8 mg/kg, the unabsorbed fraction was 0.0158 of the dose, the extent of absolute oral bioavailability (F) value was 0.0407, and the hepatic and intestinal first-pass effects were 40.0% and 34.2% of the oral dose, respectively. The low F of ondansetron in rats was mainly due to considerable hepatic and intestinal first-pass effects. The lower F of ondansetron in rats (4.07%) than that in humans (62+/-15%) was mainly due to greater hepatic metabolism of the drug in rats. Ondansetron was stable in the rat gastric juices and various buffer solutions having pHs ranging from 1 to 13. The equilibrium plasma-to-blood cells partition ratio of ondansetron was 1.74-5.31. Protein binding of ondansetron to fresh rat plasma was 53.2%.     

Pharmacokinetics of the new pyrimidine derivative NS-7, a novel Na+/Ca2+ channel blocker. 1st communication: plasma concentrations and excretions after a single intravenous 14C-NS-7 injection to rats, dogs and monkeys

Plasma concentration profiles and excretion were investigated after a single intravenous injection of 14C-NS-7 (4-(fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride, CAS 178429-67-9), a novel Na+/Ca2+ channel blocker, to rats, dogs and monkeys. Plasma protein binding of this drug was determined in vitro and in vivo. AUC0-infinity values for radioactivity and NS-7 after the intravenous administration of 14C-NS-7 to male rats increased with the dose, namely from 0.04 to 5 mg/kg (radioactivity) and from 0.2 to 5 mg/kg (NS-7), indicating the linearity of the drug's pharmacokinetics. Plasma concentrations of the unchanged drug after the intravenous injection of 0.2 mg/kg 14C-NS-7 decreased biexponentially, respective t1/2 beta values being 15.9 h in the male and 22.4 h in the female rats. The t1/2 beta values difference in the males and females might be due to sex differences in NS-7 metabolism. Urinary and fecal excretions of radioactivity within 168 h of administration were 33.0 and 61.4% of the dose in the male and 35.0 and 53.2% in the female rats. No radioactivity was detected in air exhaled from the males and females collected for 168 h after NS-7 administration. Within 24 h of administration, respective biliary excretions for the male and female rats were 26.1 and 11.9% of the dose. Of this excreted radioactivity, 34.9% was reabsorbed in the males. NS-7 plasma concentrations decreased biexponentially after intravenous administration of 0.2 mg/kg 14C-NS-7 to dogs and monkeys. The elimination half-life was 18 h for the dogs and 9.52 h for the monkeys. Urinary and fecal excretions of radioactivity within 168 h of administration were 24.2 and 70.0% of the dose for the dogs, and 63.3 and 24.8% for the monkeys. These species differences in excretion may be due to differences in urinary metabolite compositions. In vitro protein binding of NS-7 showed no marked species differences and was independent of the NS-7 concentration. Binding of 14C-NS-7 in the sera of rats, dogs, monkeys and humans was 90.7%, 73.5% 79.0% and 87.1%, respectively. Binding to human serum albumin, alpha 1-acid glycoprotein and lipoprotein was 56.2%, 45.4% and 79.5%, in the range of 4-40 ng/ml. In vivo binding in rat serum 5 min, 6 h and 24 h after the intravenous injection of 14C-NS-7(0.2 mg/kg) ranged from 89.6 to 90.6%.     

Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 microg.min/mL), total body clearance (CL (tot); 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V (ss); 7.60 +/- 1.03 and 3.61 +/- 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 microg.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % +/- 0.26 % and 5.10 % +/- 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL (tot) and V (ss) values, and were much less (0.010 % +/- 0.001 % and 0.12 % +/- 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.     

The pharmacokinetics of HI-6 in beagle dogs

The pharmacokinetics of HI-6 were studied following intravenous administration to beagle dogs (n = 7). The bioavailability of two different strength intramuscularly administered doses was also determined in the same animals. After a 20 mg kg-1 intravenous dose, the mean (+/- S.D.) initial HI-6 plasma concentration was 93.1 +/- 10.8 micrograms ml-1. The mean half-life was 48.2 +/- 17.7 min, the mean total body clearance was 5.16 +/- 0.81 ml min-1 kg-1, the mean apparent volume of distribution was 0.37 +/- 0.20 l kg-1 and 61.2 +/- 14.6 per cent of the dose was excreted as unchanged drug. The pharmacokinetic constants calculated following the 20 mg kg-1 intramuscular doses of 250 and 25 mg ml-1 solutions were not significantly different from those obtained following the intravenous dose. Also, the areas under the plasma concentration versus time curves were not significantly different indicating 100 per cent bioavailability from the intramuscular route of administration.     

Nasal absorption of procyclidine in rats and dogs

Nasal absorption of procyclidine, a synthetic anticholinergic compound, was investigated in Wistar rats and Beagle dogs. The dosing solution was prepared by dissolving 14C-procyclidine in 50% ethanolic saline. The dosing solution was administered intravenously and intranasally to rats at a dose of 0.6 mg/kg (i.e., 60 microl/kg in the form of a 1% w/v solution), and intravenously, orally and intranasally to dogs at a dose of 0.3 mg/kg (i.e., 6 microl/kg in the form of a 5% w/v solution). Blood samples were taken from an artery of the animals through the catheter for periods of 1200 (for rats) and 1,440 min (for dogs), and the radioactivity in the samples was determined by liquid scintillation counting. The nasal bioavailability of procyclidine in rats and dogs, based on the radioactivity, was calculated to be 81.1 and 98.6%, respectively. In both rats and dogs, the plasma profiles of procyclidine following nasal administration were very close to those following intravenous administration, leading to nearly superimposable profiles between the two protocols. In dogs, nasal administration resulted in significantly higher plasma concentrations during the first 30 min period compared to oral administration, suggesting the superiority of the nasal route over the oral route in terms of a prompt expression of the pharmacological effect of the drug. The results obtained in this study indicate that procyclidine is rapidly and nearly completely absorbed via the nasal route. In conclusion, nasal administration represents a viable alternative to intravenous administration in the case of procyclidine.     

Fab-bound colchicine appears to adopt Fab fragment disposition in rats.

The disposition of colchicine-specific Fab fragments and the effect of Fab fragment administration on the disposition of colchicine were studied in anaesthetized bile duct-cannulated rats. One group of rats (n = 6) received a 125I-Fab dose of 38 mg kg-1 i.v. The plasma disposition was characterized by a volume of distribution of 179 +/- 48 mL kg-1, total body clearance of 1.02 +/- 0.07 mL min-1 kg-1, t1/2 alpha of 0.17 +/- 0.03 h and t1/2 beta of 1.3 +/- 0.3 h. Fab fragments were in part excreted by the renal route (15.6 +/- 6% of the Fab dose), while biliary excretion was a minor route (< 2% of the Fab dose). Two other groups of rats received 15 micrograms kg-1 colchicine (n = 6) or 15 micrograms kg-1 colchicine plus 38 mg kg-1 colchicine-specific Fab fragments (n = 6) by intravenous infusion. Pharmacokinetics of colchicine was markedly altered in the Fab-colchicine-treated rats. In this group, distribution volume and total body clearance of colchicine were decreased by factors of 22 and 10, respectively, compared with the values in the colchicine-treated group and were very similar to those of Fab fragments. An 80% reduction of cumulative biliary excretion of colchicine was observed in Fab-colchicine-treated rats (P < 0.01). The fraction of colchicine dose excreted by the urinary route was 38 +/- 6.9 and 9 +/- 0.7% respectively in Fab-colchicine- and colchicine-treated groups (P < 0.01). These data show that during Fab treatment, colchicine followed the elimination kinetics of Fab fragments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics, tissue distribution, and excretion of buagafuran in rats

The pharmacokinetics, tissue distribution, and excretion of buagafuran (BF, 4-butyl-α-agarofuran), a promising antianxiety drug isolated from Gharu-wood (Aquilaria agallocha Roxb), were investigated in rats. BF plasma concentration was determined in rats after oral and intravenous doses by GC-TOF-MS. BF showed nonlinear pharmacokinetics after oral and intravenous administration of 4, 16, and 64 mg/kg. The AUC(0-∞) and C(max) did not increase proportionally with doses, indicating the saturation in absorption kinetics of BF in rats after oral dosage. BF absorption was extremely poor with an absolute bioavailability below 9.5%. After oral administration of (3)H-BF (4 mg/kg) to rats, radioactivity was well distributed to the tissues examined. The highest radioactivity was found in gastrointestinal tract, followed by liver and kidney. Radioactivity in brain, as a target organ, was about 20-40% of that in plasma at all time points. Total mean percent recovery of radioactive dose was about 80% in rats (51.2% in urine; 28.7% in feces). Bile elimination was also the major excretion route of BF, and 45.4% of the radioactive dose was recovered in bile.     

Pharmacokinetics of ethopropazine in the rat after oral and intravenous administration

The pharmacokinetics of the anticholinergic drug ethopropazine (ET) have been studied in the rat after intravenous (i.v.) and oral administration. After i.v. doses of 5 and 10 mg/kg ET HCl, mean +/- S.D. plasma AUC were 9836 +/- 2129 (n = 4 rats) and 13096 +/- 4186 ng h/mL (n = 5 rats), respectively. The t1/2 after 5 and 10 mg/kg i.v. doses were 17.9 +/- 3.3 and 20.9 +/- 6.0 h, respectively. The Cl and V(dss) after 5 mg/kg i.v. doses were 0.48 +/- 0.10 L/h/kg and 7.1 +/- 2.3 L/kg, respectively. Statistically significant differences were present between the 5 and 10 mg/kg dose levels in Cl and V(dss). Oral administration of 50 mg/kg ET HCl (n = 5 rats) yielded mean AUC of 2685 +/- 336 ng h/mL. Mean plasma C(max), t(max) and t1/2 after oral doses were 236 +/- 99 ng/mL, 2.2 +/- 1.4 h and 26.1 +/- 5.4 h, respectively. Less than 1% of the dose was recovered unchanged in urine and bile. Ethopropazine is extensively distributed in the rat, and has relatively slow Cl in relation to hepatic blood flow in the rat. The drug appears to be extensively metabolized in the rat, and nonlinearity is present between the 5 and the 10 mg/kg i.v. doses. The drug displayed poor bioavailability (< 5%) after oral administration.