Intestinal First-Pass Metabolism of Eperisone in the Rat

Purpose. The purpose of this study was to clarify quantitatively the contribution of the intestine to the first-pass metabolism of eperisone in rats. Methods. The systemic availabilities of eperisone were estimated by administering the drug into the duodenum, portal vein, and femoral vein in rats in vivo. The first-pass metabolism of eperisone was confirmed in the perfused rat small intestine in situ. Metabolism of eperisone to an -1-hydroxylated metabolite (HMO), the first step of eperisone metabolism, was studied using rat intestinal microsomes in vitro. Results. The bioavailabilities in the intestine were 0.176 and 0.0879 at administration rates of 100 and 25 mg/h/kg, respectively, whereas those in the liver were 0.532 and 0.486, respectively. In the intestinal perfusion experiment, the appearance clearance to the portal vein from the intestinal lumen was much lower than the elimination clearance from the intestinal lumen, resulting in high metabolic clearance of eperisone in the small intestine. Eperisone was biotransformed to HMO by rat intestinal microsomes, and this was inhibited by -naphthoflavone and an anti-rat CYP1A antibody. Conclusions. Those data strongly suggest that eperisone may be metabolized to HMO by CYP1A in rat intestinal microsomes during the first-pass through the epithelium of the small intestine.     

Effect of Co-administration of Tacrolimus on the Pharmacokinetics of Multiple Subcutaneous Administered Interferon-Alpha in Rats

Purpose  Repeated administration of exogenous proteinic compounds triggers the production of specific antibodies. This reaction is limits not only pharmacokinetic studies in animal but also development of human or humanized proteins as drugs. We investigated the effect of co-administration of tacrolimus on pharmacokinetic of human interferon-alpha (h-IFN) following multiple subcutaneous administration in rats. Methods  h-IFN was administered at a dose of 5 million IU/kg. For some experiments, tacrolimus was also either subcutaneously or intravenously injected in rats at a dose of 0.001 or 0.5 mg/kg as well as with administration of h-IFN. Results  Multiple administration of h-IFN without co-administration of tacrolimus induced IgG response at 2 or 3 weeks following first administration in the short dosing interval (daily, once per 3 days, or once per a week), irrespective of the dosing interval. Both intravenous and subcutaneous administration of tacrolimus (0.5 mg/kg) with multiple h-IFN injections successfully suppressed IgG response against h-IFN. Interestingly, in lower doses (0.001 mg/kg), intravenous co-administration of tacrolimus showed much stronger suppressive effect than subcutaneous co-administration. Conclusion  Intravenous co-administration of tacrolimus (0.001 mg/kg) may be a promising way to assess crossover pharmacokinetic study of human or humanized proteinic formulations with multiple dosing schedules in an experimental animal.     

The Relative Bioavailability and Metabolism of Bisphenol A in Rats Is Dependent upon the Route of Administration

Bisphenol A (BPA) is used to produce polymers for food contactapplications, thus there is potential for oral exposure of humansto trace amounts via the diet. BPA was weakly estrogenic inscreening assays measuring uterine weight/response, althoughmuch higher oral doses of BPA were required to elicit a uterotropicresponse as compared to other routes of administration. Theobjective of this study was to determine if a route dependencyexists in the pharmacokinetics and metabolism of ¹⁴C-labeledBPA following single oral (po), intraperitoneal (ip), or subcutaneous(sc) doses of either 10 or 100 mg/kg to Fischer 344 rats. Resultsindicated a marked route dependency in the pharmacokineticsof BPA. The relative bioavailability of BPA and plasma radioactivitywas markedly lower following oral administration as comparedto sc or ip administration. The major fraction of plasma radioactivityfollowing oral dosing was the monoglucuronide conjugate of BPA(68–100% of plasma radioactivity). BPA was the major componentin plasma at Cmax following sc or ip administration exceededonly by BPA-monoglucuronide in females dosed ip. Up to fouradditional unidentified metabolites were present only in theplasma of animals dosed ip or sc. One of these, found only followingip administration, was tentatively identified as the monosulfateconjugate of BPA. The monoglucuronide conjugate was the majorurinary metabolite; unchanged BPA was the principal componentexcreted in feces. These results demonstrated a route dependencyof BPA bioavailability in rats, with oral administration resultingin the lowest bioavailability, and offer an explanation forthe apparent route differences in estrogenic potency observedfor BPA.     

基因多态性对肾移植术后他克莫司药动学影响的研究进展

肾移植是终末期肾脏疾病有效的治疗手段,为降低肾移植术后排斥反应风险,患者术后需长期服用免疫抑制剂,他克莫司为目前最广泛应用的钙调蛋白类免疫抑制剂.然而,在临床应用中,他克莫司表现出治疗窗窄、药动学个体差异大等特点.在影响其个体间差异的相关因素中,基因多态性是目前研究的热点之一.本文通过检索文献,就常见的基因多态性对他克...     

去甲异波尔定及其代谢产物的药动学与生物利用度研究

目的 研究去甲异波尔定静脉注射和灌胃给药后,其原型药物和主要代谢物去甲异波尔定-9-O-α-葡萄糖醛酸苷在大鼠体内的药动学特征和生物利用度。方法 以SD大鼠为模型动物,采用超高效液相色谱质谱检测法测定去甲异波尔定及其葡萄糖醛酸苷的血药浓度,并计算药动学参数。结果 去甲异波尔定及其葡萄糖醛酸苷的绝对生物利用度分别为2.77%和88.6%。大鼠静脉注射给药后,去甲异波尔定及其葡萄糖醛酸苷的药动学参数t_1/2分别为(42.16±36.56)和(275.26±176.89)min,AUC_0-t分别为(55.25±22.97)和(584.57±216.18)mg·min·mL^-1,ke分别为(0.024 9±0.012 9)和(0.003 7± 0.002 4)min^-1。大鼠灌胃给药后,去甲异波尔定及其葡萄糖醛酸苷的药动学参数Cmax分别为(0.14±0.03)和(13.80± 1.46)mg·mL^-1,T_max分别为(23.33±13.29)和(45.00±9.49)min,t_1/2分别为(30.20±11.04)和(313.79±181.20)min,AUC_0-t分别为(9.17±2.44)和(3 108.69±299.45)mg·min·mL^-1,k_e分别为(0.025 2±0.007 6)和(0.002 7±0.001 0)min^-1。统计学检验表明,静脉注射和灌胃给药后去甲异波尔定及其葡萄糖醛酸苷的t_1/2、AUC_0-t、T_max、C_max、k_e和MRT之间均有显著性差异(P<0.05)。结论 去甲异波尔定在体内生物转化迅速且生物利用度低。与原型药物相比,去甲异波尔定葡萄糖醛酸苷在体内的血药浓度较高且消除缓慢。     

他克莫司在溃疡性结肠炎模型大鼠体内的药代动力学研究

目的:考察他克莫司(FK506)在葡聚糖硫酸钠(DSS)诱导的溃疡性结肠炎(UC)模型大鼠体内的药代动力学特点。方法:将12只大鼠随机分为UC组和正常组各6只,UC组给予5%DSS连续自由饮用7 d诱导建立UC模型,第8天分别给予两组大鼠灌胃FK506 1 mg/kg,于给药前和给药后不同时间点采血,测定FK506血药浓度,比较分析两组大鼠主要药代动力学参数。结果:与正常组相比,UC组体内的FK506暴露强度增加,AUC_0-t增加了44.06%,半衰期延长了1.85 h(近50%),体内滞留时间(MRT_0-∞)延长了37.0%,清除率下降了32.25%(P均<0.05)。结论:FK506在大鼠体内的药代动力学会受到UC的影响,导致FK506代谢下降,半衰期延长,暴露强度增加,可能与UC影响P糖蛋白和CYP3A酶活性有关。     

Intestinal Lymphatic Transport Enhances the Post-Prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-Pass Metabolism

Purpose  To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. Methods  Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. Results  Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3–4.9 fold increase in ) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8–20%), in spite of good absorption (72–75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. Conclusions  The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first examples of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism. Studies funded by Novartis Pharma AG.     

环丙沙星在兔体内对他克莫司药代动力学的影响

目的 :研究环丙沙星在兔体内对他克莫司药代动力学的影响 ,为临床合理用药提供参考。方法 :10只兔子随机分成两组 ,一组口服他克莫司胶囊 ,30min后静脉注射环丙沙星 ;另一组仅口服他克莫司胶囊 ,2wk后交叉给药。给药后分别于不同时间点取血 ,用ELISA法测定药物浓度 ,计算药代动力学参数。结果 :单用和与环丙沙星合用的他克莫司药代动力学参数分别为 :Cmax=(29 8±9 06)、(27 9±8 32)ng/ml ,T1/2β= (11 6±4 57)h、(12 8±3 78)h ,AUC= (251 0±78 3)、(265 7±74 6)ng/(ml·min) ;经检验 ,两者均无显著性差异 (P>0 05)。结论 :单剂量的环丙沙星在兔体内对他克莫司的药代动力学无显著影响。     

Evaluation of the Intestinal Absorption of Erythromycin in Man: Absolute Bioavailability and Comparison with Enteric Coated Erythromycin

To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 ± 0.08 (mean ± SD) hours and for the capsule was 2.92 ± 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 ± 7% and for the duodenal solution 43 ± 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 ± 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.     

谷胱甘肽片人体药代动力学及相对生物利用度

目的：测定谷胱甘肽片的药动学及相对生物利用度。方法：１０名健康男性志愿者单剂量随机交叉口服６００ｍｇ谷胱甘肽片后,经荧光分光光度法测定血浆药物浓度。结果：口服国产或进口谷胱甘肽片后血药浓度达峰时间分别为１．３５±０．２７ｈ和１．３５±０．２０ｈ,峰浓度分别为２３．１７±７．６６ｕｍｏｌ／Ｌ和２３．７９±７．１５ｕｍｏｌ／Ｌ,药－时曲线下面积分别为７３．７２±２５．１７ｕｍｏｌ／（ｈ·Ｌ）和７４．４９±１６．４９ｕｍｏｌ／（ｈ·Ｌ）。结论：结果表明两种片剂具有生物等效性。     

国产环孢素胶丸的相对生物利用度研究

目的 :比较国产与进口环孢素胶丸的相对生物利用度及药代动力学参数。方法 :12名健康男性志愿者单剂量随机交叉口服300mg 国产与进口环孢素胶丸后 ,用荧光偏振免疫分析仪测定血药浓度 ,对AUC、Cmax 和Tmax 进行等效性检验。结果 :国产与进口环孢素胶丸的AUC分别为 (10 47±1 74) μg/(ml·h)、(10 71±1 45) μg/(ml·h) ;Tmax 分别为 (1 46±0 26)h、(1 38±0 31)h ;Cmax 分别为 (1 91±0 31) μg/ml、(1 88±0 22) μg/ml ;相对生物利用度为 (97 59±9 71) %。结论 :国产与进口的环孢素胶丸剂具有生物等效性。     

Role of Intestinal First-Pass Metabolism of Baicalein in its Absorption Process

Purpose The aim of the present study was to investigate the role of intestinal first-pass metabolism of baicalein (B) in its absorption process.Methods The intestinal absorption of B was characterized using Caco-2 cell monolayer model and rat in situ single-pass intestinal perfusion model. In addition, preliminary metabolic kinetics of B was evaluated in both rat and human intestinal S9 fractions.Results B was well absorbed and extensively metabolized to baicalin (BG), baicalein-7-O-β-glucuronide, in rat intestinal perfusion model, whereas less extent of metabolism was observed in the Caco-2 cell monolayer model. Moreover, BG generated in the intestinal epithelium during the absorption of B also rapidly transported to both the apical side (the apical chamber of Caco-2 model and the perfusate of the intestinal perfusion model) as well as the basolateral side of the small intestine (the basal chamber of Caco-2 model and the mesenteric vein of the intestinal perfusion model). From the preliminary metabolic studies, it was found that a higher loading dose of B resulted in a less extent of metabolism in intestine. In addition, the extent of metabolism of B was similar in jejunum and ileum when 50 μM of B was perfused through different sections of rat small intestine.Conclusion The first-pass metabolism of B in small intestine may play an important role in its low oral bioavailability.     

补阳还五汤对高脂血症模型大鼠脂质代谢及肝组织的影响

目的:探讨补阳还五汤对高脂血症模型大鼠脂质代谢及肝组织的影响。方法:将雄性SD大鼠随机分为空白对照组、模型组、阳性对照组(辛伐他汀0.004 g/kg)和补阳还五汤低、高剂量组(3.5、14.0 g/kg,按生药总量计),每组10只。除空白对照组大鼠灌胃水外,其余各组大鼠均按体质量灌胃脂肪乳剂复制高脂血症模型。从造模第21天开始,各组大鼠上午继续灌胃水或脂肪乳剂,下午灌胃水或相应药物,连续20 d。末次给药后,检测各组大鼠血浆中三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、卵磷脂胆固醇脂酰基转移酶(LCAT)、磷脂转移蛋白(PLTP)、肝脂酶(HL)含量以及肝细胞中脂蛋白脂肪酶(LPL)、微粒体三酰甘油转运蛋白(MTP)、3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶的含量,并观察各组大鼠肝组织的病理形态学变化。结果:与空白对照组比较,模型组大鼠TG、TC、LDL-C、ALT、HMG-CoA还原酶含量均显著升高(P<0.05或P<0.01),HL、LPL、MTP含量均显著降低(P<0...     

安必林干糖浆的人体药代动力学和生物利用度研究

本文采用荧光法测定了6名健康志愿者自身交叉口服国产氨苄青霉素原料和进口安必林干糖浆后的血药浓度,按MCPKP-自动化药物动力学程序计算药动学参数和相对生物利用度,原料药和干糖浆的主要药动学参数分别为:Ka 1.45±0.86和1.33±0.60h~(-1);T_(1/2)K 1.68±0.84和1.57±0.38h;Tp 1.45±0.24和1.53±0.36h;C_(max) 6.07±1.91和6.14±2.3μg/ml;相对生物利用度F_校为1.00±0.31。     

肠道细胞色素P450和P-糖蛋白对口服药物生物利用度的影响

目的综述肠道细胞色素P450和P-糖蛋白(P-gp)对口服药物生物利用度的影响,包括CYP450、Pgp的作用及CYP与Pgp的联合作用。方法收集、阅读并分析近十年来关于肠道细胞CYP450和Pgp影响口服药物生物利用度的文献。结果 CYP450和Pgp在胃肠道均具有高表达,且两者的底物具有显著的重叠性,所以肠道细胞CYP450对已吸收药物的生物转化作用和肠道细胞中Pgp对已吸收药物的主动外排作用是影响口服药物生物利用度的重要因素。结论肠道细胞CYP450和Pgp对药物的口服生物利用度具有重要影响。     

国产交沙霉素片人体药物动力学及相对生物利用度研究

10名健康受试者交叉口服单剂量日本产及国产交沙霉素片(800mg)后,用微生物法测定血药浓度,按单室血管外模型处理分析得出各药物动力学参数。结果表明二者基本相似,其相对生物利用度为97±37%。     

头孢氨苄胶囊的人体生物等效性研究

目的研究不同厂家的头孢氨苄胶囊在人体内的生物等效性。方法对18名健屎志愿耆旱剂量口服给于不同生严厂豕的头记氨卞颗粒,以高效液相色谱法测定其血药浓度经时过程。结果受试制剂与参比制剂中头孢氨苄主要药代动力学参数达峰时间（Tmax）分别为（56．67±18．23）min和（61．67±24．62）min,峰浓度（Cmax）分别为（31．08±6．41）μg／mL和（29．95±6．56）μg／mL,0～300min药时曲线下面积（AUC0-300）分别为（3074．56±516．01）μg／（mL·min）和（3069．21±469．81）μg／（mL·min）。结论受试制剂与参比制剂具有生物等效性。     

布洛芬缓释胶囊的药物动力学及相对生物利用度

对 18名健康志愿者单剂量随机交叉口服 6 0 0mg布洛芬缓释胶囊 (A)和芬必得 (B)进行药物动力学和相对生物利用度研究。采用高效液相色谱法测定血清中布洛芬浓度 ,药物动力学参数以配对t检验与双单侧t检验进行统计分析。结果表明两种制剂的tmax、Cmax和AUC0→∞ 均无显著性差异 (P >0 0 5)。两者具有生物等效性 ,以B为标准参比制剂 ,单剂量给药时A的相对生物利用度为 (95 86± 8 95) %。     

甲苯磺酸舒他西林分散片人体生物利用度实验研究

建立了测定人血浆中氨苄西林和舒巴坦浓度的高效液相色谱 紫外检测法,采用此方法测定１０ 名健康男性志愿者单剂量交叉口服７５０ ｍｇ 甲苯磺酸舒他西林分散片（ 受试制剂） 和优立新片（ 参比制剂） 后血浆中氨苄西林和舒巴坦的浓度,发现受试者服用优立新后,血浆中氨苄西林和舒巴坦的Ｃｍａｘ 分别为（１０－３２ ±２－９４） 和（１０－１６ ±３－１３）μｇ／ｍＬ,摩尔比为０－６８∶１ ．同时考察氨苄西林和舒巴坦的药物动力学特性,进行生物等效性评价．结果为受试制剂中氨苄西林的相对生物利用度为（１１０－３ ±２０－６） ％ ;舒巴坦为（１０８－０ ±２０－１）％ ．对受试制剂和参比制剂的主要药物动力学参数进行统计学分析,结果表明２ 种制剂生物等效