Analysis of Intestinal Perfusion Data for Highly Permeable Drugs Using a Numerical Aqueous Resistance—Nonlinear Regression Method

Purpose. To develop, validate and apply a method for analyzing the intestinal perfusion data of highly permeable compounds using the Numerical Aqueous Resistance (NAR) theory and nonlinear regression (NAR-NLR) and to compare the results with the well-established Modified Boundary Layer (MBL) Analysis. Methods. The NAR-NLR method was validated and the results were compared to the MBL analysis results using previously reported cephradine jejunal perfusion data. Using the Single Pass Intestinal Perfusion (SPIP) method, the concentration dependence of intestinal permeability was investigated for formycin B, proline, and thymidine, three compounds reported to be absorbed by carrier-mediated transport processes. The MBL and NAR-NLR analyses were then applied to the three sets of SPIP data. Results. The results demonstrate that the intrinsic MBL transport parameters were highly variable and, in one case, the analyses failed to give a statistically significant Michaelis constant. The MBL mean dimensionless wall permeabilities (P*_w) were greater than the NAR-NLR P*_w and were also highly variable. In all cases, the NAR-NLR variability was significantly lower than the MBL variability. The extreme variability in the MBL-calculated P*_w is due to the sensitivity of P*_w when the fraction of unabsorbed drug (C_m/C_o) is low or, alternatively, when P*_w approached the aqueous permeability, P*_aq. Conclusions. The NAR-NLR method facilitates the analysis of intestinal perfusion data for highly permeable compounds such as those absorbed by carrier-mediated processes at concentrations below their K_m. The method also allows for the use of a wider range of flow conditions than the MBL analysis resulting in more reliable and less variable estimates of intestinal transport parameters as well as intestinal wall permeabilities.     

A recirculatory model with enterohepatic circulation by measuring portal and systemic blood concentration difference

The present study describes a recirculatory model for the evaluation of pharmacokinetic characteristics of drugs possessing enterohepatic circulation (EHC). The advantage of the model is to separately define the extent and rate of absorption for the dosage and EHC after oral administration. Cephradine was used as a model drug and was intravenously or orally administered to rats. Portal and systemic bloods were simultaneously collected in order to estimate various local moments after defining the global moments obtained by non-compartment analysis. For the zero-order moments, bioavailability (BA), the hepatic recovery ratio (F_h), the sum of the local absorption ratio for the dosage and recirculatory local absorption ratio for EHC (F^po _a), and the recirculatory local absorption ratio for EHC (F^ehc _a) after oral administration were estimated to be 95.6, 77.9, 172, and 71.5%, respectively. These data indicate that a complete absorption and substantial EHC contribute high oral exposure of cephradine. For the first-order moments, the sum of the mean local absorption times for the dosage and EHC (t¯^po _a) and the mean transit time for a single pass of EHC (t¯_c) were 2.50 and 0.117 hr, suggesting a rapid EHC of cephradine compared with the absorption from the dosage. With this model, the absorption rate-time profiles for the dosage and EHC were separately simulated by using a program of nonlinear least squares (MULTI) with fast inverse Laplace transform (FILT). The cumulative biliary excretion ratio (F_bile) calculated by the model was in good agreement with the experimental value obtained in the bile duct-cannulated rats. These results suggest that the model proposed in this study would be useful for evaluating the extent and rate of ECH along with absorption from the dosage after oral administration of drugs.     

Passive and Carrier-Mediated Intestinal Absorption Components of Two Angiotensin Converting Enzyme (ACE) Inhibitor Prodrugs in Rats: Enalapril and Fosinopril

The intestinal absorption mechanism of two ACE inhibitor prodrugs, enalapril and fosinopril, was investigated in rats using a single-pass perfusion method. A modified boundary layer solution was applied to determine the apparent intestinal wall permeability. The prodrug enalapril is well absorbed from rat jejunum, whereas the parent drug, enalaprilat, is poorly absorbed. The permeability of enalapril is concentration dependent and is decreased by the dipeptide Tyr-Gly and by cephradine but not by the amino acids L-leucine or L-phenylalanine, indicating a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast, fosinopril is readily absorbed by a concentration-independent mechanism without the involvement of the peptide carrier.     

头孢拉定致肾损害

目的监测头孢拉定对肾脏的不良反应。方法通过对文献检索和筛选,分析头孢拉定肾脏不良反应的原因,总结转归及预防。结果与结论大剂量或长期应用头孢拉定对肾脏有毒性。     

头孢拉定对甲硝唑血药浓度的影响

目的 :探讨头孢拉定与甲硝唑合并应用时 ,体内甲硝唑血浓度与药动学有否影响。方法 :家兔试验 ,分别给送服甲硝唑 2 0 0 mg,于给药后一定时间分别取血测定。间隔一周后 ,再分别送服甲硝唑 2 0 0 mg+头孢拉定 2 5 0 mg,同样时间取血分别测定血药浓度及药动学参数。结果 :头孢拉定与甲硝唑合用时 ,可使甲硝唑血药浓度升高 ,头孢拉定对甲硝唑药物动力学参数没有影响     

头孢拉定治疗感染性疾病100例

本文报道头孢拉定治疗各种感染100例,其中呼吸道感染57例,消化道感染23例及泌尿道感染20例。剂量为静滴2q,bid或口服胶囊0.5,qid,疗程平均8±SD4d。其显效率分别为42％(24/57),26％(6/23)及50％(10/20);总有效率为88％。给药1-3d临床症状如发热、尿道刺激和腹痛明显消减,呼吸道症状也随体温下降而缓解。头孢拉定对大肠杆菌、克雷白杆菌、金黄色葡萄球菌所致的感染疗效较佳,对绿脓杆菌感染无效。副反应率为15％,以恶心、呕吐为多见。     

眼内注射头孢拉定与地塞米松治疗蜡样芽胞杆菌性全眼球炎实验观察

通过兔眼内注射头孢拉定与地塞米松,并应用ERG与病理检查,观察该药物的毒性作用和对蜡样芽胞杆菌引起的暴发性全眼球炎的治疗效果。结果头孢拉定25mg/ml,地塞米松400μg/ml作玻璃体腔注射无毒性。早期应用该药物有一定的抗菌作用。反复多次给药,在控制炎症方面效果为佳。     

高压液相法同时测定头孢拉定和精氨酸的含量

目的：以HPLC外标法同时测定注射用头孢拉定中头孢拉定、精氨酸和杂质头孢氨苄的含量。方法：采用ODS-3柱,乙腈-醋酸盐缓冲液(12：88)为流动相,检测波长200nm。结果：该法能较好的分离被测组分和有关杂质,被测组分的线性关系良好,回收率满意。结论：该法专属性好,快速、准确。     

Antipseudomonal activity and nephrotoxicity of cephradine-netilmicin combination

The effects of intraperitoneal injections of cephradine in a dose of 75 mg/kg and netilmicin in dose of 50 mg/kg and their combination on creatinine and urea serum levels of rabbits were studied as well as the antipseudomonal activity against three multiresistant clinicial isolates. The antibacterial activity was investigated by two methods: Checkerboard titration method and time-kill studies. Finally, the antibacterial activity of the sera obtained from the rabbits receiving the used drugs in the previous regimen was studied using time-kill study method againstPseudomonas aeruginosa isolates. Results obtained from this study indicated that both creatinine and urea serum levels of the rabbits receiving both drugs were not significantly different from those of the rabbits receiving either cephradine or netilmicin alone. At the same time thein vitro antibactrial activity (either of the prepared solutions of the used drugs and their combination or of the sera obtained from the rabbits receiving these drugs as mentioned before) showed a synergistic effect against the tested strains ofPseudomonas aeruginosa     

头孢拉定胶囊人体药代动力学和生物等效性

目的研究头孢拉定胶囊在健康人体内的相对生物利用度和生物等效性,为新药报批及其临床应用提供依据。方法20名健康受试者随机双交叉试验方法,单剂量口服受试及参比制剂500 mg,用HPLC法测定给药后不同时间的血药浓度,计算主要药代动力学参数。结果口服头孢拉定胶囊受试制剂和参比制剂后的主要药动学参数：T1/2分别为0.841±0.165和0.842±0.213 h;Cm ax分别为（15.922±2.584）和（15.922±2.584）mg/L;Tm ax分别为（1.225±0.197）和（1.225±0.242）h;AUC0-t分别为（25.399±5.806）和（26.159±5.989）mg/（L·h）。以AUC0-t计算,与参比制剂相比受试制剂中头孢拉定的平均相对生物利用度为（97.4±7.0）%。结论两制剂生物等效。