Pharmacokinetics,metabolism and pharmacodynamic s of a benzimidazole angiotensin II type 1 receptor antagonist in the beagle dog and cynomologus monkey

1. The pharmacokinetic s and disposition of E4177, an angiotensin II (Ang II) type 1 receptor antagonist, were studied in the beagle dog and cynomologus monkey following intravenous (i.v.) and oral (p.o.) administration. The relationship between the plasma concentrations of E4177 and Ang II receptor blockade were investigated in both species.

2. Single 0.3?mg kg i.v. doses of E4177 in dog and monkey were eliminated rapidly. The elimination half-lives were 1.9 and 2.0 h, and the systematic plasma clearance values were 9.1 and 12.9 ml/min/kg respectively.

3. The oral bioavailabilityof single doses of 0.3-3?mg/kg of E4177 was > 60% in both dog and monkey. The absorption by both species was rapid, with peak plasma levels observed within 1 h, and the areas under the concentration versus time curve to infinity were proportional to the dose.

4. The apparent volumes of distributionat the steady-state were 1.0 and 1.2 l/kg in dog and monkey respectively. Tissue penetration was probably limited by the relatively high binding to plasma proteins (approximately 92.0 and 98.6% in the dog and monkey respectively).

5. Faecal excretion was the major eliminationpathway for radioactivity(approximately 90% of the dose) in both species after 1?mg/kg p.o. administration of ¹⁴C-E4177. Unchanged E4177 was the major radioactive component in the urine and faeces (0-24 h) of both species, accounting for approximately 85% of dose. In monkey, a minor metabolitein excreta and plasma was identified as the phase I metabolite M1, which is produced from E4177 by methyl- hydroxylation. M1 was not detected in dog. 6. The unbound plasma concentration versus blockade of the exogenous Ang IIinduced vasopressor response was also determined after an i.v. administrationof E4177 to dog and monkey. The relationship between the unbound E4177 concentration and the effect was highly significant in both species. The IC₅₀ of the dog and monkey were not significantly different: 2.6 and 2.7 ng/ml respectively.     

Simultaneous determination and pharmacokinetics of five bufadienolides in rat plasma after oral administration of Chansu extract by SPE-HPLC method

A sensitive and rapid solid-phase extraction-high performance liquid chromatography (SPE-HPLC) method has been developed for the determination of five bufadienolides, arenobufagin, teliocinobufagin, cinobufotalin, cinobufagin and resibufogenin in rat plasma and applied to a pharmacokinetic study in rats after oral administration of Chansu extract (Venenum Bufonis). Plasma samples were pretreated with solid-phase extraction using Extract-Clean cartridges, and the extracts were analyzed by a reversed-phase C(18) column on a HPLC system with photodiode array detection (DAD). The calibration curves were linear over the range of 0.10-1.66 microg/ml for arenobufagin, 0.03-1.20 microg/ml for telocinobufagin, 0.01-0.62 microg/ml for cinobufotalin, 0.03-0.70 microg/ml for cinobufagin and 0.02-2.57 microg/ml for resibufogenin, respectively. The limit of quantification was 1.1 ng/ml for arenobufagin, 0.3 ng/ml for telocinobufagin, 9.7 ng/ml for cinobufotalin, 8.8 ng/ml for cinobufagin, 7.7 ng/ml for resibufogenin, respectively. The established method could be easily applied to the determination and pharmacokinetic studies of five bufadienolides in rat plasma after oral administration of Chansu extract.     

盐酸关附甲素在Beagle犬体内口服药代动力学和绝对生物利用度研究

目的：采用液相色谱-质谱联用分析方法研究盐酸关附甲素在Beagle犬体内的吸收特性。方法：6只Beagle犬采用双交叉实验设计,空腹单次静脉或灌胃给予盐酸关附甲素（4mg/kg）,采集不同时间点的血样,采用LC-MS法进行血浆药物浓度测定,求算相应的药代动力学参数。结果：6只Beagle犬灌胃4mg/kg盐酸关附甲素后体内过程符合二房室模型,实测的血浆药物浓度曲线下面积AUC0-48h为（18429±7281）ng·mL-1·h,最大血浆药物浓度Cmax为（1988±972）ng/mL,达峰时间tmax为（0.8±0.7）h,末端相消除半衰期t1/2为（11.2±1.6）h。与静脉注射给药相比其绝对生物利用度F为（99.0±11.2）%,拟合求得的吸收速率常数（K01）为（7.563±4.612）/h。结论：盐酸关附甲素在Bea-gle犬体内吸收迅速且完全,临床上可考虑采用口服剂型代替注射剂以便于病人用药。     

Sensitive and selective liquid chromatography-electrospray ionization mass spectrometry analysis of ginkgolide B in dog plasma

As an important active constituent of Ginkgo biloba extract, ginkoglide B is a highly selective and competitive PAF receptor antagonist which has been widely used in clinical applications. A novel high-performance liquid chromatography-electrospray ionization mass spectromentry (LC-ESI-MS) method was developed for the determination of ginkgolide B in dog plasma. After liquid/liquid extraction with ether and high-performance liquid chromatography (HPLC) gradient separation with 0.01% of ammonia water (v/v)-methanol as the mobile phase, the deprotonized anions [M-H](-1) at m/z 423 of ginkoglide B, and [M-H](-1) at m/z 492 of internal standard (IS) glibenclamide were analyzed by LC-ESI-MS in selected ion monitoring (SIM) mode. Chromatographic separation was achieved in less than 9 min and calibration curve was linear over a concentration range of 0.1-20 ng/ml. The described assay method was successfully applied to the pre-clinical pharmacokinetic study of ginkoglide B. After intragastric administration of ginkgolide B to beagle dogs, C(max) and T(max) of ginkgolide B were 43.8 +/- 6.24 ng/ml and 0.5 h, respectively, and the elimination half-life (t(1/2)) was 2.85 +/- 0.54 h.     

Quantitative determination of spinosin in rat plasma by liquid chromatography-tandem mass spectrometry method

A sensitive method for the quantitative determination of spinosin in rat plasma was developed and validated using high-performance liquid chromatographic separation with tandem mass spectrometric detection. The analytes of interest were extracted from rat plasma samples by methyl tert-butyl ether (MTBE) after acidification with 1.0% acetic acid aqueous solution. Chromatographic separation was achieved on an Agilent Zorbax SB-C(18) (50 mm x 4.6 mm, 5 microm) using a isocratic mobile phase consisting of acetonitrile-water (30:70, v/v) with 1% isopropyl alcohol and 0.01% heptafluorobutyric acid. The flow rate was 0.2 ml/min. The column temperature was maintained at 25 degrees C. Detection was performed on a triple quadrupole tandem mass spectrometer by selected reaction monitoring (SRM) mode via electrospray ionization (ESI). The calibration curve was linear over the range of 1.00-400 ng/ml in rat plasma, with 1.00 ng/ml of the lower limit of quantification (LLOQ). The inter- and intra-day precisions and accuracy for all samples were satisfactory. The validated method was successfully applied for the pharmacokinetic study of spinosin in rat. After oral administration of 20mg/kg spinosin to rats, the main pharmacokinetic parameters of T(max), C(max), T(0.5) and AUC(0-T) were 5.33+/-0.58 h, 132.2+/-10.6 ng/ml, 4.89+/-0.37 h, 1.02+/-0.09 microg h/l, respectively.     

Determination and pharmacokinetics of isoferulic acid in rat plasma by high-performance liquid chromatography after oral administration of isoferulic acid and Rhizoma Cimicifugae extract

A simple and specific high-performance liquid chromatographic (HPLC) method with ultraviolet (UV) absorbance detection has been developed for the determination of isoferulic acid in rat plasma. The plasma samples were deproteinized with methanol after the addition of internal standard (IS) tinidazole. The analysis was performed on a Kromasil C18 column (250 mm x 4.6 mm i.d., 5 microm particle size) with acetonitrile-0.05% phosphoric acid (25:75, v/v) as mobile phase. The linear range was 0.0206-5.15 microg ml(-1) and the lower limit of quantification (LLOQ) was 0.0206 microg ml(-1). The intra- and inter-day relative standard deviations (R.S.D.s%) were less than 11.4 and 12.3%, respectively, and accuracy as relative error (R.E.%) between -6.7 and -1.1%. Mean extraction recovery was above 80%. The validated method was successfully applied to the pharmacokinetic study of isoferulic acid in rat plasma after oral administration of isoferulic acid and Rhizoma Cimicifugae extract.     

Liquid chromatography tandem mass spectrometry assay to determine the pharmacokinetics of aildenafil in human plasma

A simple, sensitive and specific liquid chromatography/tandem mass spectrometry method for the quantitation of aildenafil, a new phosphodiesterase V inhibitor, in human plasma is presented. The analyte and internal standard, sildenafil, were extracted by a one-step liquid-liquid extraction in alkaline conditions and separated on a C(18) column using ammonia:10mM ammonium acetate buffer:methanol (0.1:15:85, v/v/v) as the mobile phase. The detection by an API 4000 triple quadrupole mass spectrometer in multiple-reaction monitoring mode was completed within 2.5 min. The calibration curve exhibited a linear dynamic range of 0.05-100 ng/ml with a 10 pg/ml limit of detection. The intra- and inter-day precisions measured as relative standard deviation were within 8.04% and 5.72%, respectively. This method has been used in a pharmacokinetic study of aildenafil in healthy male volunteers each given an oral administration of one of the three dosages.     

Validation of an HPLC method for the simultaneous determination of DZ5 and its active metabolite in dog plasma and its pharmacokinetics

A validated HPLC method is described for the simultaneous determination of daidzein 7,4'-di-succinic acid mon-ester-O-ethoxy (DZ5) and its active metabolite daidzein 7,4'-dioxy-ethoxy (DZ4) in dog plasma. DZ5 and DZ4 were determined by reversed-phase HPLC (column: Hypersil C18 5 microm silica, 200 mm x 4.6 mm i.d.; eluent: 400 ml water, 500 microl 85% phosphoric acid, 600 ml methanol) and photometric detection (250 nm), with Kaempferol as the internal standard. The calibration curve was linear over the range 0.1-50.0 microg/ml in dog plasma. The average extraction recoveries were 84.6% (DZ5), 82.7% (DZ4) and the within-day and between-day precisions were less than 10.93%. The assay was applied to the analysis of samples from a pharmacokinetic study. Following the oral administration and intravenous administration of DZ5, DZ5 was eliminated rapidly from the plasma and DZ4 was found in plasma. The absolute bioavailability of total DZ5 and DZ4 was 41.5%. The method was demonstrated to be feasible for pharmacokinetic studies of DZ5 in dogs.     

反相高效液相法测定吡喹酮血药浓度的方法学研究

本文报道简单是敏的反相高效液相(RP HPLC)法分析血浆中毗喹酮(PZQ)的浓度。PZQ在四氢呋喃(或乙腈)44％、蒸馏水56％中,在E_z 265nm、E_m 285nm时具有强烈荧光,并与代谢产物和血浆提取物中有荧光的物质能基线分离,检出限量4ng。用本法测定家犬口服吡喹酮片、缓绎片和静脉注射的药代动力学。     

Quantitative determination of metaxalone in human plasma by LC-MS and its application in a pharmacokinetic study

A simple and rapid method using liquid chromatography–mass spectrometry (LC-MS) for the determination of metaxalone in human plasma has been developed and validated. Letrozole was used as the internal standard (IS). The plasma samples were simply treated with acetonitrile which allowed the precipitation of plasma proteins. The chromatographic separation was achieved on a Sapphire C₁₈ (2.1 mm × 150 mm, 5 µm, Newark, USA) column using the mobile phase (5 mM ammonium acetate containing 0.01% formic acid: acetonitrile (45:55, v/v)) at a flow rate of 0.3 ml/min. The selected ion monitoring (SIM) in the positive mode was used for the determination of [M + H]⁺ m/z 222.1 and 286.1 for metaxalone and letrozole, respectively. The standard curve obtained was linear (r² ≥ 0.99) over the concentration range of 30.24−5040 ng/ml. Meanwhile, no interfering peaks or matrix effect was observed. The method established was simple and successfully applied to a pharmacokinetic study of metaxalone in healthy Chinese volunteers after a single oral dose administration of 800 mg metaxalone. The main pharmacokinetic parameters of metaxalone were as follow: C_max, (1664 ± 1208) ng/ml and (2063 ± 907) ng/ml; AUC₀₋₃₆, (13925 ± 6590) ng/ml h and (18620 ± 5717) ng/ml h; t_1/2, (13.6 ± 7.7) h and (20.3 ± 7.7) h for the reference and test tablets, respectively. These pharmacokinetic parameters of metaxalone in healthy Chinese volunteers were reported for the first time.     

Separation and quantitative analysis of coumarin compounds from Angelica dahurica (Fisch. ex Hoffm) Benth. et Hook. f by pressurized capillary electrochromatography

A pressurized capillary electrochromatography (pCEC) method with post-column detection cell has been developed for the therapeutically important coumarins from Angelica dahurica extract. The separation of five major coumarins (xanthotoxol, osthenol, imperatorin, oxypeucedanin hydrate, byakangelicin) was optimized with respect to composition of the mobile phase, ionic strength of buffers, pH, and applied voltage. Baseline separation was achieved for the five coumarins in less than 25 min using a mobile phase of methanol-acetonitrile-phosphate buffer (pH 4.8; 15 mM) (22.5:15:62.5, v/v/v). The method showed satisfactory retention time and peak area repeatability with the first use of post-column detection cell in the pCEC instrument. Comparing to capillary high performance liquid chromatography (capillary HPLC) and conventional high performance liquid chromatography (HPLC), higher column efficiency, and shorter analysis time were achieved in pCEC. The five coumarins in the extract samples representing different stages of traditional extraction of A. dahurica were also quantitatively analyzed by pCEC. The calibration curves were linear in the range 37-129, 36-126, 12-41, 88-306, 20-69 microg/ml of the standard solutions containing the five coumarins with correlation coefficients between 0.9976 and 0.9994.     

Pharmacokinetics of cyanamide in dog and rat

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (E.C. 1.2.1.3) has been made in the beagle dog and Sprague-Dawley rat. Cyanamide plasma levels were determined by a sensitive high performance liquid chromatographic assay, specific for cyanamide. In the dog, i.v. administration of cyanamide at 1, 2 and 4 mg kg-1, produced a dose-dependent pharmacokinetic behaviour. Statistically significant changes were observed in plasma clearance values (12.6 to 19.7 mL kg-1 min-1), half life values (39 to 61 min) and mean residence times (50 to 79 min). Peak plasma concentrations, after oral administration of 4 mg kg-1 were achieved at 30 min and oral bioavailability was about 65%. In the rat after i.v. or oral administration, cyanamide (2 mg kg-1) had a half life of 30 min, a total plasma clearance of 117 mL kg-1 min-1 and a mean residence time of 26 min. Oral bioavailability was about 69%.     

Effects of Various Coumarins from Roots of Angelica dahurica on Actions of Adrenaline, ACTH and Insulin in Fat Cells

Experiments were carried out on the effects of various coumarins on the actions of adrenaline, adrenocorticotropic hormone (ACTH) and insulin in fat cells isolated from rats. Furocoumarins such as oxypeucedanin hydrate, bergapten, xanthotoxin, imperatorin, phellopterin activated adrenaline-induced lipolysis. Furocoumarins such as oxypeucedanin hydrate, imperatorin and phellopterin also activated ACTH-induced lipolysis. On the other hand, furocoumarins such as byak-angelicin, neobyakangelicol and isopimpinellin strongly inhibited insulin-stimulated lipogenesis. Therefore, the crude drug "Byakushi" may activate the actions of lipolytic hormones and selectively inhibit the effects of anti-lipolytic hormones.     

A newly developed precise and sensitive radioimmunoassay for clonidine

A new precise and sensitive radioimmunoassay for clonidine has been developed. Synthesis and analysis of the hapten (4-carboxy-clonidine; St 1984) as well as antibody production in rabbits are described in detail. At a final dilution of 1:1000 the resulting immune serum binds 50% of a tritiated clonidine standard containing 1 ng of clonidine. The detection limit of the presented radioimmunoassay for clonidine is 0.1 ng/ml. The coefficient of variation did not exceed 4.3% for any of 7 standard determinations with 5 replicates. There was no relevant cross-reactivity of inactive clonidine metabolites apart from 4-OH-clonidine. To avoid any errors from cross-reaction clonidine was selectively and quantitatively extracted into diethylether from unknown plasma samples. Following concentration of the extracts even such low concentrations as 20 pg of clonidine/ml plasma were detectable. With the radioimmunoassay applied in pharmacokinetic studies a maximal clonidine concentration in blood plasma of healthy human volunteers was determined to 0.6 ng/ml 1.5 h after oral administration of 150 micrograms.     

Rodent pharmacokinetics and receptor occupancy of the GABAA receptor subtype selective benzodiazepine site ligand L-838417

The pharmacokinetics of L-838417, a GABAA receptor subtype selective benzodiazepine site agonist, were studied in rats and mice after single oral (p.o.), intraperitoneal (i.p.) and intravenous (i.v.) doses. In both species L-838417 was well absorbed following i.p. administration and whilst in rats p.o. bioavailability was good (41%), in mice it was negligible (<1%), precluding this as a route of administration for mouse behavioural studies. Despite having a similar volume of distribution (ca 1.4 l/kg) in rats and mice, L-838417 was cleared at twice liver blood flow in mice (161 ml/min/kg) and moderately cleared in rats (24 ml/min/kg), potentially explaining the poor oral bioavailability in mice. Finally, as a pharmacodynamic readout the benzodiazepine binding site occupancy was determined in rats (0.3-3 mg/kg, p.o.) and mice (1-30 mg/kg, i.p.) using a [3H]Ro 15-1788 in vivo binding assay. Although the resulting dose-occupancy relationship for both species demonstrated a dose-dependent increase in receptor occupancy, appreciable variability was observed at low dose levels, potentially making interpretation of behavioural responses difficult. In contrast, a clear relationship between plasma and brain concentrations and receptor occupancy were determined suggesting the observed dose-occupancy variability is a consequence of the pharmacokinetic properties of L-838417. The plasma and brain concentrations required to occupy 50% of the benzodiazepine binding sites were similar in both rats (28 ng/ml and 33 ng/ml g, respectively) and mice (63 ng/ml and 53 ng/ml g, respectively), with a non-linear concentration response observed with increasing doses of L-838417. These studies demonstrate the importance of utilizing pharmacokinetic/receptor occupancy data when interpreting pharmacodynamic responses at a given dose.     

Simultaneous determination of Gastrodin and Ligustrazine hydrochloride in dog plasma by gradient high-performance liquid chromatography

A novel reversed-phase HPLC method was developed for the simultaneous determination of Gastrodin (Gas) and Ligustrazine hydrochloride (LZH) in dog plasma after oral administration of the preparation 'Tianxiong Capsule'. The assay involves deproteinization, extraction and subsequent detection with a gradient solvent system at two different wavelengths. Retention times were 10.6 and 18.9 min for Gas and LZH, respectively. Linear responses were observed over a wide range (0.40-200.0 microg/ml for Gas and 0.0999-39.96 microg/ml for LZH) in plasma. The mean intra- and inter-assay variation coefficients were 2.7 and 3.4% for Gas and 3.4 and 4.2% for LZH, respectively. The average extract recoveries were 76.77% for Gas and 75.8% for LZH. This assay has been successfully used to provide pharmacokinetic data for Gastrodin with oral administration of Tianxiong capsules.     

Mexiletine in acute myocardial infarction. Simulation of a theoretical protocol and validation in six patients

A mexiletine (Mexitil, MEX) administration schedule was established by simulation, in order to maintain MEX at therapeutic levels in plasma during the transition from parenteral to slow-release MEX (SR MEX) administration. This protocol was made valid in 6 patients with acute myocardial infarction (AMI) admitted to a coronary care unit, 24 h after the onset of pain. From both the i.v. and oral plasma level data, the pharmacokinetic parameter alterations of MEX and its hydroxymethylmexiletine metabolite (OH MEX) were evaluated over a week's period. The results presented here demonstrate that a twice daily oral SR MEX administration, starting at the end of MEX infusion, maintains the therapeutic concentrations of MEX (750-2000 ng/ml) previously achieved by infusion therapy (at 48 h, end of infusion, mean +/- SD = 1393 +/- 325 ng/ml; at 60 h, mean +/- SD = 1434 +/- 376 ng/ml; at 96 h, mean +/- SD = 1423 +/- 367 ng/ml. No evidence of either clinical side-effects or malignant arrhythmias was observed. MEX and OH MEX pharmacokinetic parameters were estimated by fitting the i.v. infusion data (phase I) and the oral data after the last SR MEX administration (phase II)beta to a linear compartment model. The terminal half-life t1/2 MEX was longer in phase I than in phase II (28.4 +/- 12.1 h (betaI) versus 14.06 +/- 4.47 h (II); p less than 0.01). This prolonged t1/2 MEX was probably due to a decrease of total plasma clearance Cl MEX (3.723 +/- 1.534 ml.kg-1min-1 (I) versus 5.031 +/- 1.28 ml.kg-1min-1 (II).(ABSTRACT TRUNCATED AT 250 WORDS)     

HPLC assay of Lidocaine in plasma with solid phase extraction and UV detection

A sensitive and reliable method based on solid-phase extraction and reversed-phase liquid chromatography was developed and validated for the quantitation of Lidocaine (Lid) in dog plasma. Phenacemide was used as an internal standard (IS) in the extraction which employed C18 solid-phase extraction cartridges. The washing and eluting solutions were 2 ml acetonitrile-pH 9.0 phosphate buffer (10:90 v/v) and 0.5 ml acetonitrile-pH 4.0 phosphate buffer (40:60 v/v). respectively. The eluent obtained from the cartridge was directly analyzed on a reversed-phase ODS column with UV detection at 210 nm. A clean chromatogram and high sensitivity were achieved at this wavelength. The mobile phase was acetonitrile and pH 5.9 phosphate buffer (20:80 v/v). The retention times were 6.4 and 7.2 min for Lid and IS, respectively, at a flow rate of 1.0 ml min(-1). The mean absolute recovery was 96.6% (n = 9) with a CV of 3.8% for Lid and 81.7% with CV of 2.5% (n = 3) for IS. The limit of quantitation was 20 ng ml(-1), with the intra- and inter-day precisions (n = 5) of 4.4 and 3.4%, respectively, and the intra- and inter-day accuracies (n = 5) of -4.3 and -5.0%, respectively. For the analyses of Lid in spiked plasma samples at 20, 100 and 200 ng ml(-1), the overall mean intra- and inter-day precisions (n = 15) were 3.9 and 4.9%, respectively, and the overall mean intra- and inter-day accuracies (n = 15) were -3.7 and -4.6%, respectively. The correlation coefficients for calibration plots in the range 20-1000 ng ml(-1) in plasma were typically higher than 0.998. The suitability of the method was demonstrated by the study in a beagle dog receiving a low intravenous dose of Lid.     

Simultaneous GC-MS determination of nicotine and cotinine in plasma for the pharmacokinetic characterization of nicotine in rats

A gas liquid chromatography/mass spectrometry assay method was developed for the simultaneous determination of nicotine and its major metabolite, cotinine, in rat plasma. Of particular interest was improving the low and variable extraction recovery for the parent drug and the metabolite. In addition, the feasibility of this assay method for pharmacokinetic studies of nicotine and cotinine after intravenous (i.v.), oral, and intraperitoneal (i.p.) administration of 1 mg kg(-1) of nicotine was tested. The low (30 and 48% for nicotine and cotinine, respectively) and variable (25 and 22% coefficient of variation for nicotine and cotinine, respectively) extraction recovery for nicotine and cotinine into dichloromethane was significantly improved by the addition of NaCl to the plasma. As a result, the recoveries for nicotine and cotinine were improved to 68 and 65%, respectively. The coefficient of variation was less than 10% in the 50-500 ng ml(-1) range and less than 16.58% at 10 ng ml(-1) for both nicotine and cotinine, indicating that the reproducibility of the assay was also improved by the extraction procedure. When injected intravenously at a dose of 1 mg kg(-1), the temporal profile of plasma concentration for nicotine followed a bi-exponential decline. Moment analysis revealed that pharmacokinetic parameters for nicotine (i.e. Cl, 46.30 ml min(-1) kg(-1); Vss, 2.77 1 kg(-1)) was similar to those reported in studies using 14C-nicotine. Absolute bioavailabilities of nicotine for i.p. and oral administration were 87.0 and 80.4%, respectively. The concentration of the metabolite increased up to 4 h to reach Cmax after i.p. and oral administrations and then declined slowly with time. These results indicate that this convenient analytical procedure is readily applicable to pharmacokinetic studies of nicotine and cotinine involving small laboratory animals with a sensitivity comparable with that reported for studies using 14C-nicotine.     

大黄酸在大鼠和比格犬体内的吸收动力学研究

目的：研究中药大黄的活性蒽醌单体大黄酸（rhein）在SD大鼠和Beagle犬体内的吸收动力学特征,为临床的进一步研究提供基础参数和依据。方法：采用HPLC-荧光检测法分别测定SD大鼠和Beagle犬在灌胃及静脉注射两种给药途径下单次给予不同剂量的大黄酸药物后,两种动物血浆样品中的大黄酸经时曲线过程并计算相应的药代动力学参数及绝对生物利用度。结果：SD大鼠灌胃及静脉注射高、中、低剂量大黄酸后,AUC与剂量间呈一定的线性关系（r〉0.99）,灌胃及静脉注射3个剂量下的半衰期结果相似。在上述研究范围内大黄酸在大鼠体内的药代动力学行为近似是线性的。用面积法,算得高、中、低3个剂量下大黄酸在大鼠体内的绝对生物利用度分别为16.4%、23.8%、19.4%。对6只Beagle犬进行随机交叉试验,静脉注射大黄酸真溶液（0.4mg/kg）和灌胃大黄酸混悬液（20mg/kg）,算得静注及灌胃后药物的消除半衰期分别为（1.77±0.93）、（3.25±0.80）h,Beagle犬体内的绝对生物利用度为（49.7±7.4）%。对Beagle犬组（6只）和SD大鼠灌胃3剂量组（18只）各只动物生物利用度进行方差分析,结果显示差异具有统计学意义（P〈0.01）。结论：大黄酸在不同动物间吸收存在一定的种属差异,吸收程度在Bea-gle犬体内略高于在大鼠体内。