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The rat single-pass intestinal perfusion model was applied to study the effect of CYP3A and P-glycoprotein on the absorption of buagafuran in lumen of rats. Buagafuran concentrations in intestinal perfusate and blood in vena mesenterica collected at different time points after perfusion were determined by GC-MS. Permeability coefficient of buagafuran was calculated by the equation [P(lumen) = -(Q/2pirl)Ln(C(out)/C(in)) and P(blood) = (deltaM(B)/deltat)/(2pirl)]. The effects of troleandomycin (TAO, CYP3A inhibitor), cyclosporin A (CYP3A/p-glycoprotein inhibitor) on the absorption of buagafuran in lumen were observed. After rat single-pass intestinal perfusion, the cumulative amount of buagafuran in mesenteric vein of rat was 73.4, 82.9, and 98.3 pmol x cm(-2) and were increased 3.9, 4.6, and 5.6 fold by addition of inhibitor of P-gp (LSN335984), CYP3A (TAO) or P-gp and CYP3A (CsA), respectively. Moreover, the metabolized fraction of buagafuran was decreased by 12%, 11% and 21% with inhibitors. The results suggested that the poor bioavailability of buagafuran was mostly due to the interplay of P-gp and CYP3A on the absorption, transport and metabolism of buagafuran in intestine of rats.

To study the effect of P-glycoprotein (P-gp) on the absorption of buagafuran in ileum, the concentration of buagafuran in Caco-2 cells, rat averted intestinal sacs and recirculating perfusion were determined by UV-HPLC method. Verapamil and cyclospirin A (CsA) were used as P-gp inhibitors. The results showed that the transportation of buagafuran across Caco-2 monolayer showed vectorial manner. The permeation of buagafuran from apical (A) to basolateral (B) side was 11% and 24.8% from B to A side. Verapamil and CsA were found to increase the transport of buagafuran by 1.4 and 1.35 fold from A to B side and decrease by 71% and 75% from B to A side, respectively, compared with control. The uptake of buagafuran in Caco-2 cell was also enhanced by P-gp inhibitors, especially in low concentration of buagafuran. Ninety percent of buagafuran was absorbed after 90 min perfusion. Verapamil and CsA were found to improve the absorption of buagafuran at all time points, especially at 30 min (12.4% and 21.5%, respectively). During the incubation, only 14% of buagafuran left in rat averted intestinal sacs, while buagafuran levels were increased in both intestine homogenate and sacs by adding verapamil and CsA. The results indicated that buagafuran was one of the P-gp substrates based on the present study. The absorption of buagafuran can be blocked by P-gp, resulting in the enhancement of buagafuran metabolism in intestine. The poor bioavailability of buagafuran may be partially due to the effect of P-gp on its absorption and transportation in intestinal lumen.

To establish a high performance liquid chromatography (HPLC) coupled with tandem mass spectrometry quantitative detection method for the determination of curcumol, the main ingredient of zedoary turmeric oil fat emulsion, and investigate its pharmacokinetics in Beagle dogs, nine healthy Beagle dogs were divided into three groups, and blood samples were collected at scheduled time points after intravenous injection of 7.5, 10 and 12.5 mg x kg(-1) zedoary turmeric oil fat emulsion. The concentrations of curcumol were determined and pharmacokinetics was calculated. A good linearity was obtained from 0.25 to 100 ng x mL(-1) in plasma. The relative recoveries were from 91.33% to 103.17%, and the absolute recoveries were from 31.61% to 37.20%. The intra-day and inter-day variances (RSD) were < 15%. The main pharmacokinetic parameters of curcumol after intravenous injection of 7.5, 10 and 12.5 mg x kg(-1) zedoary turmeric oil fat emulsion were as follows, T1/2 : (2.0 +/- 0.4), (1.7 +/- 0.2) and (2.3 +/- 0.8) h, AUC(0-infinity): (15.1 +/- 2.7), (18.3 +/- 2.0) and (29.5 +/- 4.0) ng x mL(-1) x h; MRT: (0.9 +/- 0.1), (0.8 +/- 0.2) and (0.8 +/- 0.1) h, CL: (21.9 +/- 4.0), (24.9 +/- 6.0) and (18.4 +/- 1.2) L x h(-1) x kg; Vd : (65.4 +/- 26.5), (62.0 +/- 13.4) and (61.2 +/- 19.8) L x kg(-1), respectively. The developed method was rapid, highly sensitive and specific and could be used in curcumol pharmacokinetic studies in vivo. A three-compartment model was best fit to the plasma concentration--time curves obtained in Beagle dogs and the plasma AUC was increased proportionally with doses.

Aim: The feasibility of intranasal brain targeting drug delivery system via the olfactory pathway from nose to brain was explored., Methods: Using gellan gum, a cation-sensitive gel forming excipient, huperzine A (Hup A) nasal in situ gel was prepared by pH gradient precipitation method. The pharmacokinetics of Hup A in blood and cerebrospinal fluid (CSF) after intranasal, intravenous and intragastric adminstration to rats was studied using cisternal cannulation for serial CSF sampling and femoral artery cannulation for serial blood sampling. The distributions of Hup A into rat brain tissues following intranasal dosing were compared with those after intravenous and intragastric dosing by tissue homogeneization. The therapeutics effects of Hup A nasal in situ gel on cognitive function were tested in mice and rats with Morris water maze, step down test and step through test., Results: The AUC(0-->6 h) value in plasma obtained after nasal administration was 0.94 of that after intravenous administration, but the AUC(0-->6 h) of CSF after nasal administration was 1.3 and 2.3 times of that after intravenous and intragastric administration. The AUC(0-->6 h), of cerebrum, hippocampus, cerebellum, left olfactory bulb and right olfactory bulb after nasal administration were 1.5, 1.3, 1.0, 1.2 and 1.0 of that after intravenous administration, 2.7, 2.2, 1.9, 3.1 and 2.6 times of that after intragastric administration, respectively. Intranasal adminintration of 17.5-35 microg x kg(-1) showed equal effects after oral adminintration of 70 microg x kg(-1) commercial tablets, which was in good agreement with the results of pharmacokinetics., Conclusion: Intranasal administration of huperzine A nasal in situ gel significantly increased the distributions of Hup A into rat brain tissues, especially into cerebrum and hippocampus which should be the target areas of Hup A, and enhanced the brain targeting of Hup A.

Aim: To investigate the effect of preparation technique on in vitro release mechanism of huperzine A-PLGA microspheres., Methods: Huperzine A-PLGA microspheres were prepared by two kinds of O/O emulsion solvent evaporation method (method A and B). In vitro release mechanism was explained by release profile, degradation rate and swelling rate of microspheres in vitro. The microspheres morphology and drug distribution within microspheres were observed in order to explain further the drug release mechanism., Results: The encapsulation efficiency of huperzine A microspheres prepared by method A and B was 47.60% and 83.50% respectively. Microspheres prepared by method A could sustain release for 35 days with nearly no initial burst release. The release profile fitted well to zero order equation and drug release mainly through degradation and diffusion mechanism. Huperzine A microspheres prepared by method B could sustain release for 21 days with some evidence of initial burst release. The release profile fitted well to the Higuchi equation and drug release was mainly through diffusion mechanism., Conclusion: Huperzine A microspheres prepared by method A had more desirable release profile.

Aim: To investigate the excretion of beta-elemene from the respiratory tracts in male Spraque-Dawley rats., Methods: After a single administration of beta-elemene to rats at the dosage of 75 mg x kg(-1) (i.v. or i.p.), the exhaled gases were collected and concentrated at various time points. The residues were analyzed by gas chromatography., Results: A minor amount of unchanged beta-elemene was excreted via rat respiratory tracts after iv and ip administration of a single dose. The cumulative excretion were 1.41% and 0.51% respectively., Conclusion: The results demonstrated that unchanged beta-elemene excretes from rat respiratory tracts, but may not be the main elimination pathway in rats.

Aim: To study the absorption of zedoary oil in intestine of rat., Methods: In situ single pass perfusion model was used and the concentrations of three components in perfusate were determined by HPLC in combination with diode array detection., Results: The P(app) s of curcumol, curdione and germacrone were all low and had no significant difference (P > 0.05) at zedoary oil concentration of 0.4, 0.8 and 1.2 mg x mL(-1) in transmucosal fluid or in four different regions of intestine of rat [duodenum, jejunum, ileum, colon]. The absorption rates of germacrone and curdione were faster than curcumol's in this study., Conclusion: The zedoary oil concentration in transmucosal fluid had no significant effect on the P(app) s within the scope of 0.4-1.2 mg x mL(-1). The absorption of curcumol, curdione and germacrone showed the passive diffusion process, and didn't contain a special absorption window.

Aim: To develop a capillary gas chromatographic method for the determination and pharmacokinetic study of patchouli alcohol in rat plasma after iv administration., Methods: The drug was extracted with ethyl acetate. Eugenol was used as internal standard. The separation was carried out on a HP-5MS quartz capillary column, with high-purity nitrogen as carrier gas and flame ionization detector (FID) as detector. The column temperature was maintained at 80 degrees C for 1 min and then programmed to 200 degrees C at a rate of 15 degrees C x min(-1); it was held at 200 degrees C for 1 min, and then programmed to 290 degrees C at a rate of 60 degrees C x min(-1); the final temperature was held for 1 min. The temperature of both injector and detector was set at 290 degrees C., Results: The standard curve was linear from 25 to 5 000 microg x L(-1) in rat plasma. The recovery of this method was from 90.0% to 110.0% with satisfactory relative standard deviation (RSD) less than 10.0%. The pharmacokinetic parameters demonstrated patchouli alcohol were consistent with the two-compartment open model and showed linear pharmacokinetics. The T1/2beta, AUC and MRT of patchouli alcohol in patchouli oil were all higher than that of patchouli alcohol., Conclusion: This method is quick, precise and reliable. The pharmacokinetics of patchouli alcohol is different from that of patchouli alcohol in patchouli oil.

Artenibenzoate is a new schistosomacide. This paper reports the pharmacokinetics of artenibenzoate in rats after oral administration. The concentrations in biological samples were detected by spectrophotometry. The concentration-time curve of the drug in plasma showed a double-peak after 150, 300 and 600 mg.kg-1 ig. Artenibenzoate absorption was fast and peak plasma level was found 1 h after administration. Then, the drug level declined to the lowest in 8 h. A second absorption peak appeared in 12 h. Two hours after oral administration to normal rats, the highest level of artenibenzoate was present in the stomach wall, while appreciable level was found in testicle, liver, spleen, heart, kidney and lung. Artenibenzoate in fat and intestine was lower, almost no drug was detected in brain and muscle. Six hours after oral administration, the drug concentration in various tissues decreased rapidly, but that in testicle, heart, kidney and fat decreased slowly. Urinary excretion was an important route of excretion. Artenibenzoate excreted in urine was about 45.6% of the administered dosage and that in feces 24.8% within a 48 hours period. The excreted amount in bile was 0.54% within 36 hours. Plasma protein binding of artenibenzoate was about 70%. Major unchanged artenibenzoate was detected in the extract from plasma, major reduced-arteannuin from feces, and both unchanged artenibenzoate and reduced-arteannuin from urine after oral administration in rats.

Qinghaosu (QHS), also known as artemisinin and arteannuin, is a novel type of sesquiterpene with a peroxide linkage isolated from the Chinese herb Artemisia annua L. Since its discovery as an antimalarial with low toxicity, hundreds of derivatives have been synthesized among them artesunate (ATS), artemether (ATM) and dihydroqinghaosu (DHQHS) were found to be more active than QHS itself. A suppository of QHS, a dual-pack dosage form of ATS (artesunic acid to be dissolved in sodium bicarbonate solution just before iv injection) and an oil solution of ATM for im injection had been approved by our Ministry of Health for clinical use. However, a preparation for oral administration is still not available. We have reported that when dogs were given QHS tablets orally at the dose of 70 mg/kg, no drug was detected in the serum using the RIA method, whereas appreciable serum concentration was found by the same method when dogs were given DHQHS tablets at a dose as low as 10 mg/kg. This paper reports the pharmacokinetics of DHQHS in man studied with the RIA method and compared with QHS. When DHQHS in tablet form was given to human volunteers at doses of 1.1-2.2 mg/kg, peak serum levels of 0.13-0.71 micrograms/ml were obtained in 1.33 h with MRT of 2.26-2.36 h. When QHS tablets were given at the dose as high as 15 mg/kg, however, the peak serum level found in 1.5 h was only 0.09 microgram/ml with MRT of 1.33 h. Therefore, the bioavailability of QHS tablets is only 1.62-10.08% that of DHQHS.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of artesunate (AS) was studied in 3 cows, single dose of AS (5 mg/kg) were administered intravenously and the drug concentrations were determined by means of a TLC method developed in our laboratory. The plasma drug concentration-time course of AS, after the treatment with a pharmacokinetic microcomputer program MCPKP edited by Wen-Jiang Xia, was found to be best fitted to a two compartment open model and its pharmacokinetic parameters were as follows, T1/2 alpha = 2.43 min, T1/2 beta = 31.45 min, V1 = 0.124 L/kg, VB = 0.937 L/kg, ClB = 0.0215 L/kg. min, AUC = 236 mg/L.min. Dihydroartemisinine (DHA), the main active metabolite of AS in the bodies, was detected simultaneously. Peak plasma concentration of 3.5 micrograms/ml of DHA was reached at about 3 minutes after dosing and the AUC was 82 mg/L.min.

Qinghaosu (QHS), also known as artemisinine and arteannuin, is isolated from the Chinese herb Artemisia annua L. It is highly active against both chloroquine-sensitive and chloroquine-resistant strains of P. berghei and has been approved by the Ministry of Health for the treatment of malaria. When QHS is treated with sodium borohydride, dihydroqinghaosu (DH QHS) is resulted with the antimalarial activity enhanced several fold. This paper reports the pharmacokinetics of DHQHS studied with the radioimmunoassay method. When the drug was given orally in tablet form to rabbits at doses of 10, 20 and 30 mg/kg, peak serum levels of 0.03, 0.05 and 0.13 micrograms/ml, respectively, were obtained in 1 to 2 h. The corresponding T1/2 of the drug were found to be 1.19, 1.00 and 1.10 h and the MRTs were 1.73, 1.36 and 1.53 h. No significant difference between dosages used was observed. When dogs were given DHQHS tablets at the dose of 20 mg/kg, a peak serum concentration of 0.13 micrograms/ml wes reached in about 2 h with a T1/2 of 2.10 h and an MRT of 3.04 h. However, when dogs were given QHS tablets at the dose of 70 mg/kg, no drug was detected in the serum. It would appear that the bioavailability of DHQHS tablets is much higher than that of QHS when given orally to the dog.

Dihydroartemisinine (DHA) is a derivative of qinghaosu(artemisine), which is an antimalarial drug. DHA was given to mice inoculated with Plasmodium berhgei ANKA strain by intramuscular injection. Within proper dose range, the dose-effect and time-effect curves of DHA against the malaria can be described by y = 4.9960 + 2.9536 x and y = 7.2654 - 0.3414 t, respectively, where y is the estimated value of parasitemia suppressing rate in probit; x is log dose; t is the period since drug administration im. Accordingly, the ED50 = 1.00 +/- 0.13 mg/kg and the time of half-effect was 6.6 h, when the dose was 5.0 mg/kg im. The elimination rate constant of the effective dose in vivo was 0.2662h-1 with a half-life of 2.6 h.

Qinghaosu, also known as artemisinin and arteannuin, is a new type of antimalarial drug isolated from Artemisa annua L. Its low solubility in water and oil limited its widespread clinical use. Artesunate (sodium dihydroqinghaosu hydrogen hemisuccinate monoester) is easily soluble in water and is used iv in the treatment of acute cerebral and malignant malaria. However, artesunate was shown to have a very short half-life when given iv in animals as well as in human beings. A transdermal dosage form of artesunic acid had been prepared and was reported to have reliable suppressing and killing effects on plasmobium berghei in mice. This paper reports results of pharmacokinetic studies of this preparation when applied onto a fixed area of the shaved skin of mice and rabbits. Serum concentration of the drug was determined by a method of radioimmunoassay. The drug was found to be easily absorbed from the skin. The serum concentration-time curve is depicted in figures 1. Peak concentration of 1.8 micrograms/ml was reached at about 2 h when a dose of 25 mg/kg was given to rabbits. For mice, peak serum concentrations of 2.05 and 7.11 micrograms/ml were attained in about 0.5 h after doses of 31.3 and 71.4 mg/kg, respectively, while at a dose of 6.7 mg/kg a peak level of 0.82 micrograms/ml (a concentration more than 5000 times the IC50 of artesunate in in vitro tests on plasmodium berghei for antimalarial activity) was attained at about 4 h after application of the drug. The half-lives of the drug were found to be more than 2 h for both mice and rabbits.