Depside salts from Salvia miltiorrhiza improve myocardial microperfusion in rats using laser Doppler flowmetry

Aim： To investigate the effects of depside salts from Salvia miltiorrhiza on myocardial microperfusion and systemic hemodynamics in open-chest anaesthetized Sprague-Dawley rats. Methods： Myocardial microperfusion was measured by laser Doppler flowmetry with a needle probe; cardiac output （CO） was determined using ultrasonic Doppler flowmetry. Other hemodynamic parameters, including femoral artery blood pressure, cardiac inotropy, and systemic vascular resistance （SVR） were simultaneously recorded by the PowerLab system. Results： Intravenous administration of S miltiorrhiza depside salts resulted in a significant imme- diate increase in CO and cardiac inotropy, but a fall in SVR. S miltiorrhiza depside salts （30 mg/kg and 60 mg/kg） promoted cardiac index （CI） by 12.2%±6.3% （P〈0.01 vs baseline） and 20.1%±3.5% （P〈0.01）, respectively. Myocardial microperfusion maximally increased by 6.3%±2.9% （P〈0.01） and 9.6%±4.0% （P〈0.01） for 30 mg/kg and 60 mg/kg S miltiorrhiza depside salts, respectively. Conclusion： These results indicated that S miltiorrhiza depside salts improved myocardial microperfusion, as well as CO.     

Pharmacokinetics,tissue distribution and excretion of coumarin components from <Emphasis Type="Italic">Psoralea corylifolia</Emphasis> L. in rats

Coumarin components from Psoralea corylifolia L. are novel drugs in which psoralen and isopsoralen are the active components. The pharmacokinetics, tissue distribution and excretion of the two compounds were studied by liquid chromatography-tandem mass spectrometry after intravenous administration to Wistar rats. The elimination half-lives of psoralen and isopsoralen were 4.88 and 5.35 h. After dosing, the area under the curves of the tissues decreased in the following order: liver > lung > heart > kidney > spleen > brain for psoralen; and kidney > lung > liver > heart > spleen > brain for isopsoralen. After dosing, 51.27% of psoralen and 56.25% of isopsoralen were excreted as prototype, and urine was the major excretion route. In addition, the pharmacokinetics of psoralen and isopsoralen after oral administration to Wistar rats were also studied. The elimination half-lives of psoralen and isopsoralen were 4.13 and 5.56 h, and their relative bioavailabilities were 61.45% and 70.35%. Overall, the results show that coumarin components from P. corylifolia L. have high oral bioavailability, they are rapidly and widely distributed into tissues after intravenous administration, but they are slowly cleared and excreted.     

Pharmacokinetics and tissue distribution of gentiopicroside following oral and intravenous administration in mice.

The pharmacokinetics and tissue distribution of Gentiopicroside (GPS), one of the major active components of the Gentiana species of medicinal plants, was studied following oral and intravenous administration in mice. The distribution of GPS in mice after oral and intravenous doses could be fitted to a two-compartments open model. The serum half-life of GPS was 6.1 h and 2.8 h for intravenous and oral administration, respectively. The Tmax of GPS after oral administration was 0.50 h, and the bioavailability was 39.6%. The AUC gradient in individual tissues following intravenous administration was kidney >serum >liver >spleen >lung >thymus >fat >heart >muscle >stomach >intestinal >brain. The MRT gradient was muscle >serum >lung >spleen >lung >intestinal>heart >stomach >brain >liver >thymus >kidney >fat. Overall the data show that GPS could be absorbed rapidly in mice, but with a low bioavailability, and could distribute to tissues extensively, but was generally cleared quickly with short MRTs. The study demonstrates the need for repeated dosage, or better, a slow release formulation as an ideal means of administering GPS.     

Pharmacokinetics of lithospermic acid B isolated from Salvia miltiorrhiza in rats

The absorption and pharmacokinetics of an active component of Salvia miltiorrhiza, lithospermic acid B (LSB), was investigated after intravenous and oral administration of doses of 10 or 50 mg LSB/kg to rats. Concentrations of LSB were determined by a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay method. After intravenous administration of 50 mg/kg, dose-normalized (10 mg/kg) area under the curve (AUC) (993 microg.min/ml) was significantly greater than that at 10 mg/kg (702 microg.min/ml). The slower clearance Cl-at 50 mg/kg could be due to saturable metabolism of LSB in rats, and this could be supported by significantly slower Cl(NR) and significantly greater 24-h urinary excretion of LSB at 50 mg/kg than at 10 mg/kg. Following oral administration of LSB, the extent of LSB recovered from the entire gastrointestinal tract at 24 h ranged from 41.2% to 23.3%. Although LSB was not detected (limit of quantitation 10 ng/ml) in plasma after oral dose of 10 mg/kg, the absolute oral bioavailability at 50 mg/kg was 5%. Since LSB was shown to have low permeability through the Caco-2 cell monolayers, the low bioavailability of LSB could be due to poor absorption and metabolism.     

Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats

Magnolol (M) is a polyphenol antioxidant abundant in the bark of Magnolia officinalis Rehder & E. Wilson, a popular Chinese herb. To understand the pharmacokinetics and bioavailability of M, Sprague-Dawley rats were intravenously injected with a bolus of M (20 mg/kg) and orally given a single dose and seven doses of M (50 mg/kg). Blood samples were withdrawn via cardiopuncture at specific times. Organs including the liver, kidney, brain, lung, and heart were collected at 30 min after the 7th oral dose. The serum and tissue specimens were assayed by HPLC before and after hydrolysis with β-glucuronidase and sulfatase. The results showed that after intravenous bolus, the systemic exposure of magnolol glucuronides (MG) was comparable with that of M while after oral administration, magnolol sulfates/glucuronides (M S/G) were predominant in the bloodstream. Conversely, M was predominant in the liver, kidney, brain, lung, and heart. Among the studied organs, the liver contained the highest concentrations of M and MG. In conclusion, M S/G was the major form in circulation, whereas M was predominant in the liver, kidney, brain, lung, and heart after oral administration of M; among these organs, the liver contained the highest concentrations of M and MG.     

Disposition of cocaine in fatal poisoning in man

A fatal case of intravenous (IV) cocaine administration is presented. Cocaine tissue concentrations (mg/kg) in descending order were: kidney, 26; spleen, 22; brain, 14; heart, 6.1; skeletal muscle, 6.1; lung, 3.4; liver, 1.6; and adipose, 1.0. Body fluid cocaine concentrations (mg/L) were: urine, 39; bile, 10; vitreous humor, 2.4; and blood, 1.8. These results are in excellent agreement with cocaine tissue distribution in the dog following IV administration and limited tissue data in previously reported cocaine fatalities in man.     

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.     

甘糖酯在小鼠体内的药代动力学研究

用同位素标记法研究了[~3H]甘糖酯1次灌胃后在小鼠体内的药代动力学,其血药浓度——时间曲线符合一室开放模型。小鼠灌服[~3H]甘糖酯25mg/kg(4.48MB_q/kg)后的药动学参数为:t_(1/2)Ka 0.24h;t_(1/2)β67h,V_d921mL,Cl9.58ml/h,AUC41.45mg/(mL·h),F79.3％,PPB54.9％。该药广泛分布于肝、肾、脾、胸腺、肾上腺、肺、心、肌肉和脑内。主要经尿道与粪便排泄。     

Evaluation of the pharmacokinetics,tissue distribution and excretion studies of YMR-65, a tubulin polymerization inhibitor with potential anticancer activity,in rats using UPLC-MS/MS

1. YMR-65, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a new tubulin polymerization inhibitor with encouraging anticancer activity.

2. The validated ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) method was successfully applied to the pharmacokinetics, tissue distribution and excretion study of YMR-65 after oral and intravenous administration. The area under concentration-time curve (AUC_0-∞) for YMR-65 were 151.67?±?54.48 and 459.45?±?49.23?ng/ml*h for oral and intravenous administration at the dosage of 1.5?mg/kg, respectively and the oral bioavailability was about 33.01%. Moreover, YMR-65 was extensively distributed in heart, liver, spleen, lung, kidney, stomach, intestine and testis and the highest were detected in heart, followed by stomach, intestine and liver. The majority of YMR-65 was excreted via feces and its accumulative excretion ratio during the period of 96?h was 19.83?±?3.01%, but only 1.54?±?0.37 and 0.215?±?0.026% for urine within 96?h and bile within 10?h after intravenous administration, respectively, though the fecal and urine excretion were incomplete within 96?h.

3. In summary, this study defined the pharmacokinetic characteristics of YMR-65 in vivo and the important data can be a useful resource for further research and development.     

Organomegaly and histopathology in an animal model of mucopolysaccharidosis induced by suramin

Summary The trypanocidal drug suramin causes glycosaminoglycan and sphingolipid accumulation in the rat, thus simulating a mucopolysaccharidosis (Constantopoulos et al. 1980). In this paper we report on the extent and nature of the morphological changes that occur in the liver, kidneys, spleen, heart, lung and brain as a result of short or long term suramin administration.The first group of rats received a single intravenous injection of suramin (500 mg/kg) and was sacrificed 3–9 days after the injection. The second group received low doses of suramin (50–90 mg/kg) at 2–3 weekly intervals over 3 months. Samples of the above mentioned organs were processed for light and electronmicroscopy and the remainder of the tissue weighed and assayed for total protein, DNA and RNA content.In both groups of rats, suramin caused an abnormal enlargement of the spleen, kidney, lung and liver, splenomegaly being the most pronounced. The total protein, and DNA content did not alter in the treated rats, however, the RNA content of the spleen increased 100%, 9 days after injection and there was a small but consistent increase in RNA content of the liver, kidney and lung. Significant pathological changes were observed in these organs and also in the brain and heart. The changes were similar in many respects to the pathology seen in the lysosomal storage disorder, mucopolysaccharidosis and further support the proposition that the suramin treated rat might be a useful experimental animal model of the disease. Several mechanisms by which suramin might produce organomegaly in the rat are discussed.     

Pharmacokinetics of phenobarbital and propylhexedrine after administration of barbexaclone in the mouse

The antiepileptic barbexaclone is the salt of the base propylhexedrine (indirect sympathomimetic) and phenylethylbituric acid. After i.v. and oral administration of 66 mg/kg barbexaclone to mice the time course of propylhexedrine and phenobarbital concentrations was studied in plasma, brain, lung, liver, kidney, spleen, heart, and skeletal muscle. Furthermore, the kinetics of phenobarbital were studied after treatment with an equimolar dose of phenobarbital-Na (40 mg/kg). In contrast to the i.v. bolus of phenobarbital-Na, barbexaclone was non-lethal only when infused over a period of 3 min. After the i.v. administration of either salt, phenobarbital plasma levels declined monoexponentially with a half-life of 7.5 h; the volume of distribution was 0.78 l/kg. After oral application absorption of phenobarbital was complete with both salts, though it was delayed after barbexaclone. The latter was the result of a delayed gastro-intestinal passage. Brain uptake of phenobarbital was a slow process, equilibrium with plasma concentrations being reached only 30 min after injection. Propylhexedrine reduced phenobarbital concentrations in brain as evident from steady state tissue-plasma ratios. This was observed after i.v. as well as after oral application. After i.v. application of barbexaclone the following pharmacokinetic parameters for propylhexedrine were determined: t0.5 alpha 0.31 h, t0.5 beta 2.5 h, Vd beta 19.3 l/kg; bioavailability (AUC oral/AUC i.v.) 0.37. Propylhexedrine penetrated the blood-brain barrier rapidly. High but unequal tissue accumulation was observed: lung = kidney greater than liver = brain greater than spleen greater than heart greater than skeletal muscle.     

Postmortem distribution of sildenafil in histological material

This study reports results of the detection and quantitation of sildenafil (Viagra) in biological fluids and tissues and its stability in fixed tissues and formalin solutions in which the tissues were fixed. Toxicological analyses were performed on samples from a 60-year-old man who died of acute heart failure due to myocardiosclerosis. Sildenafil pills were found in his pocket. At the time of autopsy, sildenafil was found in body fluids and tissues (blood 0.04 mg/L, bile 0.99 mg/L, gastric contents 6.84 mg/L, urine 9.60 mg/L, brain 6.43 mg/kg, heart 6.10 mg/kg, kidney 4.28 mg/kg, liver 5.46 mg/kg, lung 5.38 mg/kg, spleen 1.38 mg/kg). Tissue samples were preserved in formalin solutions for four weeks. Analyses of formalin-fixed tissues and formalin solutions in which the same tissues had been preserved allowed the detection and quantitation of sildenafil (brain 2.20 mg/kg, formalin from brain 4.01 mg/L; heart 1.46 mg/kg, formalin from heart 4.41 mg/L; kidney 0.98 mg/kg, formalin from kidney 3.19 mg/L; liver 2.19 mg/kg, formalin from liver 3.21 mg/L; lung 1.02 mg/kg, formalin from lung 4.18 mg/L; spleen 0.28 mg/kg, formalin from spleen 0.94 mg/L). Results indicate that sildenafil has good stability in biological specimens subjected to chemical fixation.     

Pharmacokinetics of mebudipine, a new calcium antagonist, following single intravenous and oral administrations in rats

The pharmacokinetics of a new calcium antagonist, mebudipine, was studied after a single intravenous (0.5 mg/kg) and oral (10 mg/kg) administration to rats. After intravenous dosing, the plasma concentration of mebudipine declined biexponentially with a terminal half-life of 2.84 h. The blood clearance was 1.67 l/h/kg and the volume of distribution at steady state was found to be 6.26 l/kg. After oral dosing (10 mg/kg), the C(max) of mebudipine was 25.9+/-9.79 ng/ml. The oral bioavailability was low (< 2%) suggesting a marked first-pass effect. The distribution of mebudipine into some tissues such as brain, heart, liver and kidney following intravenous administration (0.5 mg/kg) was studied and a rapid distribution of mebudipine into these tissues was found. It was concluded that brain, heart, liver and kidney are in the same compartment as plasma (central).     

Enantioselective Pharmacokinetics of Homochlorcyclizine: Disposition of (+)- and (–)-Homochlorcyclizine after Intravenous and Oral Administration of Racemic Homochlorcyclizine to Rats

Abstract— Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine and stomach of rats after drug administration were determined by high-performance liquid chromatography on a chiral stationary phase. After intravenous administration (10 mg kg^?1), homochlorcyclizine was rapidly distributed in many tissues, with the highest concentration in lung. No differences were found between enantiomers in blood concentrations. After oral administration (50 mg kg^?1), the concentrations of the (+)-isomer in nearly all tissues were higher than those of the (–)-isomer. The AUC_0-x values of the (+)- and (–)-isomers differed significantly. The absorption of racemic homochlorcyclizine from rat small intestine was not enantioselective. These results suggested that the different concentrations between enantiomers after oral administration were not caused by enantioselective absorption or distribution but rather by preferential first-pass metabolism of the (–)-isomer in the liver. The enantioselectivity of metabolism was also demonstrated by in-vitro experiments.     

Bioavailability,tissue distribution,and excretion characteristics of the novel carbonic anhydrase inhibitor tolsultazolamide in rats

Aim： Tolsultazolamide, a novel carbonic anhydrase inhibitor, is designed for the prophylaxis and treatment of acute mountain sickness. The aim of this study was to investigate the pharmacokinetics, tissue distribution, and excretion characteristics of tolsultazolamide and the sex difference in pharmacokinetics in rats. Methods： For pharmacokinetic study, rats were intravenously injected tolsultazolamide at I and 2 mg/kg or orally administered tol- sultazolamide at 20, 40, or 80 mp=/kg） in a pharmacokinetic study. The concentrations of tolsultazolamide in plasma were determined with high-performance liquid chromatography, with a liquid-liquid extraction. For tissue distribution study, tolsultazolamide （80 mpJkg） was orally administered to overnight fasted rats （six per group and three per sex）. Samples were collected from the brain, heart, lung, liver, spleen, muscle, kidney, stomach, fat, intestines, pancreas and sexual gland. For excretion study, tolsultazolamide （40 mg/kg） was orally administered to 6 rats （three per sex）. The urine, feces, and bile samples were collected at 24, 48, and72 h. Results： After its intravenous administration, tolsultazolamide was rapidly eliminated from the plasma, with T~/2 of about 60-90 min. The AUCo_t and the initial concentration （CO） values were proportional to the intravenous doses. After its oral administration, tolsult- azolamide showed dose-independent pharmacokinetic characteristics, with Tmax and T~/2 of approximately 2 h and 5-7 h, respectively, and good oral absolute bioavailability of about 60%. Tolsultazolamide was distributed widely in various tissues. The highest tolsult- azolamide levels were detected in the stomach, intestine, spleen, lung, and kidney. Total excretion of unchanged tolsultazolamide in the urine, feces, and bile was less than 2%. The Cm,x and AUC of tolsultazolamide were significantly higher in female rats than those in male rats. Clearance and volume of distribution were greater in male rats than those in female rats. The oral absolute bioavailability was also significantly different between female rats （about 83%） and male rats （about 37%）. Conclusion： Tolsultazolamide was well absorbed and widely distributed in the rat, and very little of the unchanged form was excreted. Sex had a significant effect on the pharmacokinetics of tolsultazolamide.     

HPLC analysis and pharmacokinetic characteristics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, in rats and beagle dogs

We investigated the pharmacokinetic characteristics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration in rats and beagle dogs. We developed an HPLC-based method to analyze ID-6105 levels in plasma, bile, urine, feces, and tissue homogenates and validated the method in a pharmacokinetic study. The plasma concentration of ID-6105 decreased to below the quantifiable limit (0.02 microg/ml) at 4 and 8 h after i.v. administration in rats at doses of 2 and 10 mg/kg, respectively (t(1/2,alpha) and t(1/2,beta) of 0.78 and 17.8 min at a dose of 2 mg/kg, 0.91 and 176 min at a dose of 10 mg/kg, respectively). The AUC increased with nonlinear pharmacokinetics following the dosage increase from 2 to 10 mg/kg in rats, while the pharmacokinetics were not significantly altered in beagle dogs following a dosage increase from 0.5 to 2.5 mg/kg. Of the various tissues tested, ID-6105 was mainly distributed in the lung, spleen, kidney, adrenal gland, and liver after i.v. bolus administration. ID-6105 levels in the lung or kidney 2 h after i.v. bolus administration were comparable to the initial plasma concentration. However, the ID-6105 concentrations in various tissues 48 h after i.v. bolus administration became too small to measure. The cumulative amounts of ID-6105 found in the bile 48 h after the administration of 2 and 10 mg/kg were calculated to be 26.7 and 18.5% of the initial dose, respectively. The corresponding values in the urine 72 h after i.v. administration were 4.33 and 3.07% of the initial dose, suggesting that ID-6105 is mostly excreted in the bile. In conclusion, our observations indicate that ID-6105 was rapidly cleared from the blood and transferred to tissues such as the lung, spleen, kidney, and liver 2 h after i.v. bolus administration. Moreover, the majority of ID-6105 appears to be excreted in the bile by 24 h after i.v. bolus administration.     

Differential retention of doxorubicin in the organs of two strains of rats

Fluorescence microscopy and high pressure liquid chromatography were used to study the decrease of doxorubicin (DXR) concentrations in the liver, spleen, heart, lung, kidney and skeletal muscle of two strains of rats at various times after a single intravenous injection of the drug (8 mg kg-1). DXR was located within the cell nucleus and was mostly undegraded, it persisted, especially in heart, lungs and spleen where it was detectable 10 days after injection. The DXR/DNA ratio, was used as an index of nuclear fixation of the drug. A major difference in the DXR/DNA ratio between the two strains were observed in heart and spleen results; the DXR/DNA ratio was significantly higher in heart and spleen compared with lung, liver and kidney in both strains.     

玳玳果黄酮降脂提取物体内组织分布规律及特征研究

目的：建立UPLC-MS/MS分析方法同时测定玳玳果黄酮降脂提取物效应组分新橙皮苷和柚皮苷在大鼠10种脏器组织中含量，分布规律及特征。方法：采用UPLC-MS/MS技术建立提取物效应组分新橙皮苷及柚皮苷在大鼠心、肝、脾、肺、肾、脑、胃、小肠、脂质、肌肉组织中的定量分析方法；大鼠给药后分别于0.33，0.67，1，4，8 h的5个时间点，分别摘取以上10种脏器组织，测定脏器组织及血液中效应组分的质量浓度，采用DAS（V 2.0）药动学软件对各样本的药物浓度-时间数据进行房室拟合，并计算不同组织效应组分的药-时曲线下面积（AUC）及平均滞留时间（MRT）。结果：所建立的UPLC-MS/MS定量分析方法具备良好的专属性、标准曲线及线性范围良好、方法准确度与精密度、定量下限均符合有关规定；玳玳果黄酮降脂提取物效应组分在血液中的分布符合一室模型，除肾脏及脑组织外，其余脏器中提取物效应组分的房室特征多为静脉注射的二室模型，柚皮苷在肾脏中的拟合结果为非静脉注射的二室模型，新橙皮苷在脑组织拟合结果为静脉注射的三室模型，给药后8 h各组织中效应组分新橙皮苷及柚皮苷AUC值大小顺序均为小肠 > 胃 > 肾 > 脂质 ≈ 脾脏 > 肺 > 肌肉 > 肝 > 心 > 脑，效应组分在各脏器中均无明显蓄积；效应组分在血液、肾脏、肝脏中的滞留时间较长，MRT均大于2 h，脂质最短，MRT不足1 h；各脏器中新橙皮苷的药-时曲线下面积约是柚皮苷的3倍，而心、肝、肾中则是3.5，2.1和3.4倍。结论：玳玳果黄酮降脂提取物效应组分在大鼠组织中分布迅速，达峰时间早于血液；效应组分在肠道内消除缓慢，给药8 h后在各脏器中的含量均显著下降且无特异的蓄积部位。研究结果揭示玳玳果黄酮降脂提取物效应组分在大鼠体内的分布特征及规律，为进一步理解玳玳果黄酮降脂提取物在体内的作用靶点及机制奠定了基础。     

Pharmacokinetics and metabolism of lithospermic acid by LC/MS/MS in rats

The pharmacokinetics and metabolism of lithospermic acid (LA), a component isolated from Salvia miltiorrhiza, and its two O-methylated metabolites (3′-monomethyl- and 3′,3″-dimethyl-lithospermic acid), were analyzed by a rapid and specific isocratic liquid chromatography-tandem mass spectrometry (LC/MS/MS) method. Rat serum samples collected after intravenous and oral administration were analyzed for obtaining pharmacokinetic data of LA. Two O-methylated metabolites, namely one 3′-monomethyl- and one 3′,3″-dimethyl-lithospermic acid were detected in rat serum and bile samples after intravenous and oral administration of LA, respectively. An oral bioavailability of 1.15% was found, with the AUC_0–t values of 301.89 and 3.46 mg h/L for intravenous and oral administration, respectively. The total recovery from bile was 75.36% (0.46% for LA, 17.23% for M1, and 57.67% for M2) after intravenous administration, and 4.26% (0.00% for LA, 0.10% for M1, and 4.16% for M2) after oral administration. These results indicate that methylation is the main metabolic pathway of LA, and that LA is excreted into rat bile and finally into feces.     

Percutaneous absorption of rosmarinic acid in the rat

Rosmarinic acid (RA) is a nonsteroidal anti-inflammatory agent. The purpose of the study was to investigate the transdermal absorption of RA, its tissue distribution and absolute bioavailability. In ex vivo experiments, permeation of RA across excised rat skin was about 8 times higher from alcoholic solution than from water, indicating that ethanol may act as sorption promoter. The flux from water or alcoholic solution was 4.4 or 10 micrograms/cm2/h, and the tleg was 7.8 or 3.7 h, respectively. After I.V. administration, RA is best described by a 2-compartment open model; t1/2 = 1.8 h, t1/2 alpha = 0.07 h, V tau = 2.3 L/kg, V beta = 15.3 L/kg. Upon topical administration of RA in form of a W/O ointment (25 mg/kg, 50 cm2), the absolute bioavailability was 60%. 0.5 hours after I.V. administration, RA was detected and measured in brain, heart, liver, lung, muscle, spleen and bone tissue, showing the highest concentration in lung tissue (13 times the blood concentration), followed by spleen, heart and liver tissue. 4.5 hours (peak time) after topical administration of about 3 mg on the hind leg over 20 cm2, RA was measured in blood, skin, muscle and bone tissue. The percutaneous route of administration seems to be a promising one for the therapeutic use of RA as nonsteroidal anti-inflammatory agent.