Distribution kinetics of salicylic acid in the dual-perfused rat liver preparation.

The hepatic distribution kinetics of salicylic acid was determined using a single-pass dual hepatic artery (HA) and portal vein (PV) perfused in situ rat liver preparation. Bolus doses of [14C]salicylic acid and of reference markers ([3H]-water and [14C]-sucrose) were injected in a random order into either the HA or PV and then, after an appropriate interval, into the alternate vessel. The hepatic outflow profile of [14C]salicylic acid displayed a characteristic sharp peak followed by a slower eluting tail, whereas sucrose and water displayed unimodal outflow profiles. The biphasic outflow profile indicates that the hepatic distribution of salicylic acid is not instantaneous but is limited by a permeability barrier. The in situ permeability surface area product for [14C]salicylic acid was 3.35 +/- 0.26 ml/min/g for PV and 7.45 +/- 1. 50 ml/min/g for HA administration. Furthermore, theory dictates that hepatic uptake is influenced by both perfusion and permeability if effective permeability surface area product/blood flow ratio lies between the values of 0.06 and 7.0. Our estimates (3.0 for venous output and 6.7 for arterial input) indicate that hepatic uptake of salicylic acid is dependent on both perfusion and permeability. The volume terms were calculated using two different methods, standard and specific. Regardless of the compound and method, the volume of distribution after arterial administration was larger than that after venous administration. In addition, a volume of distribution approximately twice that of the total aqueous space (i.e., HA, 2.23 +/- 0.13 versus 1.10 +/- 0.07 ml/g; PV, 1.72 +/- 0.16 versus 0.68 +/- 0.04 ml/g) implies that salicylic acid has a significant affinity for hepatic tissue. A similar tissue-to-perfusate partition coefficient associated with HA and PV input (5.40 +/- 0.38 versus 6. 48 +/- 0.56) indicates that affinity of salicylic acid for hepatic tissue is independent of the route of input.     

A dispersion model of hepatic elimination: 3. Application to metabolite formation and elimination kinetics

A dispersion model of hepatic elimination is presented to describe metabolite formation and elimination kinetics within the liver, consistent with the known physiology and biochemistry of this organ. The model is based on the spread in residence times of blood flowing through the liver. This dispersion model is shown to be more consistent with transient and steady-state data obtained after the single passage of phenacetin and acetaminophen through the liver (both normal and retrograde perfusions) than other models of hepatic elimination. The dispersion model is suitable for the evaluation of enzyme heterogeneity using experimentally obtained metabolite data.     

A dispersion model of hepatic elimination: 3. Application to metabolite formation and elimination kinetics

A dispersion model of hepatic elimination is presented to describe metabolite formation and elimination kinetics within the liver, consistent with the known physiology and biochemistry of this organ. The model is based on the spread in residence times of blood flowing through the liver. This dispersion model is shown to be more consistent with transient and steady-state data obtained after the single passage of phenacetin and acetaminophen through the liver (both normal and retrograde perfusions) than other models of hepatic elimination. The dispersion model is suitable for the evaluation of enzyme heterogeneity using experimentally obtained metabolite data.     

The kinetics of urethane elimination in the mouse

Data from several investigators suggest that the prevalence of urethane-induced lung adenomas in the mouse is more nearly linearly related to the square of the urethane dose than to the dose itself. However, the relationship between urethane dose and integrated internal exposure to urethane has not been established. Outbred male Swiss mice between 41 and 45 days old were injected ip with one of seven doses of urethane ranging from 0.4 to 1.8 mg/g. The rate of elimination of urethane from the blood was followed by assaying the ethanol liberated from urethane by alkaline hydrolysis. The results indicated that urethane elimination is saturable, and saturated at all doses used, with a Vmax of 0.087 mg/ml/hr. Thus, internal exposure to urethane, measured as the area under the blood concentration, time curve, is not linearly related to urethane dose. In the range of doses used in this study, the area under the curve is C0(2)/2Vmax or (D/VD)2 (1/2Vmax), where C0 is the initial concentration; D, the dose; and VD, the volume of distribution. This relationship can be used to predict internal exposure to urethane as a function of dose.     

Effect of probenecid on the formation and elimination kinetics of the sulphate and glucuronide conjugates of diflunisal

The effect of probenecid on the pharmacokinetics of diflunisal and its glucuronide and sulphate conjugates was studied in 8 healthy volunteers. Diflunisal 250 mg b. d. was administered p. o. for 15 days and its steady state pharmacokinetics was evaluated on Day 16 after the last dose (control phase). Probenecid 500 mg b. d. was co-administered throughout the entire study period in the treatment phase of the study.The steady state plasma concentration of diflunisal was significantly higher during the probenecid treatment phase as compared to the control phase (104.0 vs. 63.1 g·ml^–1). This was the result of a significant decrease in the plasma clearance of diflunisal from 5.8 (control) to 3.4 ml·min^–1 (probenecid co-administration). The metabolite formation clearances of both glucuronides were significantly decreased by probenecid, -45 % and -54 % for the phenolic and acyl glucuronide, respectively. The metabolite formation clearance of the sulphate conjugate was not affected by probenecid co-administration.Steady state plasma concentrations of the sulphate and glucuronide conjugates of diflunisal were 2.5- to 3.1-fold higher during probenecid co-administration, due to a significant reduction in the renal clearance of the three diflunisal conjugates. Probenecid also reduced the plasma protein binding of diflunisal, but only to a minor extent; the unbound plasma fraction of diflunisal at steady state averaged between 5 and 30 % higher during probenecid co-administration.     

反相高效液相色谱法同时测定复方水杨酸洗剂中水杨酸和间苯二酚的含量

目的　建立测定复方水杨酸洗剂中水杨酸和间苯二酚含量的高效液相色谱法。方法　采用反相C18色谱柱,以乙腈 甲醇 水(10∶5∶85 )为流动相,流速: 1. 0mL·min-1,检测波长为 278nm。结果　水杨酸与间苯二酚的线性范围均为 300 ~900μg·mL-1,水杨酸r=0. 999 6,平均回收率为 100. 24%,RSD为 0. 83%;间苯二酚r=0. 9995,平均回收率为 99. 97%,RSD为 1. 02%.结论　该方法简便准确,可同时测定复方水杨酸洗剂中水杨酸及间苯二酚的含量。     

Comparative formation, distribution, and elimination kinetics of diphenylmethoxyacetic acid (a diphenhydramine metabolite) in maternal and fetal sheep.

Deamination to diphenylmethoxyacetic acid (DPMA) is the major route of diphenhydramine (DPHM) clearance in many species. In this study, we assessed the contribution of this pathway to nonplacental DPHM elimination and disposition of DPMA in maternal and fetal sheep. Paired maternal-fetal experiments were conducted in five chronically catheterized pregnant sheep (124-140 days gestation) with an appropriate washout period in between. Both maternal and fetal dosing experiments involved administration of an i.v bolus of deuterium-labeled DPMA ([2H10]-DPMA) combined with a 6-h infusion of DPHM (or a bolus of unlabeled DPMA with an infusion of deuterium-labeled DPHM). Maternal and fetal arterial plasma and urine samples were collected and analyzed for DPMA, [2H10]-DPMA, DPHM, and deuterium-labeled DPHM concentrations using gas chromatography-mass spectrometry. The preformed DPMA (or [2H10]-DPMA) had a substantially lower clearance (maternal: 0.55 +/- 0.18 versus 40.9 +/- 14.0 ml/min/kg; fetal: 0.37 +/- 0.11 versus 285. 6 +/- 122.2 ml/min/kg) and steady-state volume of distribution (Vdss, maternal: 0.10 +/- 0.02 versus 2.1 +/- 1.1 l/kg; fetal: 0.40 +/- 0. 06 versus 13.1 +/- 3.1 l/kg) as compared with the parent drug. The contribution of DPMA formation to maternal and fetal DPHM nonplacental clearance in vivo was 1.78 +/- 2.12% and 0.87 +/- 0.56%, respectively, indicating that DPMA formation is not a major route of DPHM clearance in fetal or maternal sheep. The recoveries of DPMA (or [2H10]-DPMA) in maternal urine were 88.0 +/- 6.5 and 92.1 +/- 7. 4% of the administered dose during maternal and fetal dosing experiments, respectively. Thus, this metabolite does not appear to be secondarily metabolized in fetal or maternal sheep. These findings are in contrast to other species (dog, rhesus monkey, human) where DPMA and its conjugates constitute approximately 40 to 60% of the total DPHM metabolites.     

Ion-pair formation as a strategy to enhance topical delivery of salicylic acid

An in-vitro study was carried out to determine the possibility of improving the efficiency of transdermal delivery of salicylate through human epidermis by ion-pair formers (alkylamines and quaternary ammonium ions). Further, the relationship between the physicochemical properties of the counter-ions and salicylate flux was examined. It was found that flux can be related to the conductivity associated with the penetrant solution, molecular size of the counter-ion and lipophilicity expressed as either octanol/water partition coefficient of the ion pairs or the carbon chain-length of the counter-ions. Equations have been developed to predict salicylate flux from these physicochemical parameters.     

HPLC法测定水杨酸苯酚洗剂中苯酚和水杨酸的含量

目的:建立HPLC法分离测定水杨酸苯酚洗剂中水杨酸和苯酚的含量.方法:色谱柱为Shim-packCLC-CN柱,柱温:40℃,流动相为甲醇-水(28:72),以冰醋酸调节pH至5.0;检测波长为277nm.结果:水杨酸和苯酚的线性范围分别为10.0～500.0μg/mL(r=0.999 9)和10.0～200.0μg/mL(r=0.999 9),平均回收率分别为100.9%和100.8%.结论:本方法简便、准确,可用于水杨酸苯酚洗剂的质量控制.     

Cytotoxicity,mutagenicity, and antimutagenicity of the gentisic acid on HTC cells

Gentisic acid (GA) exhibits antioxidant, anti-inflammatory, and antibiotic activities. This substance can be found in citrus fruits, grapes, olive oil, and peas. Considering that there are few studies in the literature on the toxicity of GA, the present work aimed to investigate its cytotoxic, mutagenic, and antimutagenic activities on HTC cells. GA was diluted in culture medium at the final concentration of 0.08, 0.16, 0.8, 1.6, and 8?μg/mL. The cytotoxicity was determined by the MTT assay and Trypan Blue exclusion method, with methyl methanesulfonate and doxorubicin as positive controls, respectively. The cytokinesis-block micronucleus assay determined the mutagenic/antimutagenic activity with benzo[a]pyrene as positive control. Negative control received culture medium only. GA (0.08–8?μg/mL) was not cytotoxic to HTC cells by the MTT assay nor the Trypan Blue exclusion method as no statistical difference was observed when compared to the control. Concentration of 0.08 and 0.8?μg/mL showed no mutagenic or clastogenic effects, as no significant micronuclei inductions were observed, different from 8?μg/mL, that was mutagenic. Furthermore, none of the concentrations presented an antiproliferative activity. The antimutagenic activity of GA (0.08?μg/mL) was observed at the simultaneous treatment, as it reduced the frequency of micronuclei by 76% (24?h) and 79% (48?h). Although pre- and post-treatments were not statistically different from the mutagen, they reduced the induced-damage by 11% and 21%, respectively. The present study indicated the absence of cytotoxicity and antiproliferative activities of GA, in addition to their antimutagenic/protective effects that may contribute to human health.     

高效液相色谱法测定鞣柳硼三酸散中水杨酸的含量

目的:探讨用反相高效液相色谱法测定鞣柳硼三酸散中水杨酸的含量。方法:采用Symetry Shield RP18(5μm 4.6mm×250mm)Columm色谱柱;以0.05mol/L磷酸二氢钠缓冲液(pH2.6)-乙腈(50∶50)为流动相;检测波长233nm。结果:水杨酸在20.4～61.2μg/ml浓度范围内呈良好的线性关系,平均回收率为99.0%。结论:本法简便、准确、快速,适用于鞣柳硼三酸散中水杨酸的含量测定。     

RP-HPLC法同时测定浓苯甲酸水杨酸软膏中苯甲酸和水杨酸的含量

目的建立同时测定新型浓苯甲酸水杨酸软膏中苯甲酸和水杨酸浓度的RP-HPLC法。方法采用Kromasil-C₁₈（150 mm×4.6 mm,5μm）色谱柱;流动相为V（甲醇）:V(0.02 mol·L^-1,KH₂PO₄溶液,磷酸调pH=3.1)=50:50;检测波长280nm;流速1.0 mL·min^-1;柱温20℃。结果苯甲酸、水杨酸进样质量浓度分别为96～144 mg·L^-1（r=0.999 5）、48～72 mg·L^-1（r=0.999 7）时具良好线性关系,加样回收率分别为99.6%～100.6%、99.4%～100.2%,批间、批内RSD为0.3%～0.7%。结论本方法简便、精确、重现性好,适用于测定新型浓苯甲酸水杨酸软膏中苯甲酸和水杨酸浓度。