Elimination of azlocillin in patients with biliary t-tube drainage

Summary The pharmacokinetic of azlocillin was followed in five elderly patients after biliary surgery. Total clearance was 138.6±17.7 ml/min when 2.0 g was given as an i.v. bolus injection. The half-life of the -phase averaged 110 min. The total clearance and the half-life of azlocillin were influenced by slight impairment of renal function (creatinine clearance 59.4±13.6 ml/min). In patients with normal liver function biliary excretion of the drug amounted to 5.3±2.8% of the dose (n=3) and the kinetics of biliary excretion were linear. In contrast, in two patients with impaired liver function biliary excretion was 0.2% and 0.5% of the dose, and kinetic analysis of biliary excretion rates revealed at least one zero order step in the excretion process. Renal excretion of the drug amounted to 45.0±17.7% of the dose, which means that 50% of the total clearance of azlocillin has to be accounted for by metabolic clearance.     

Biliary excretion of diflunisal conjugates in patients with T-tube drainage

Summary The urinary and biliary excretion of diflunisal and its glucuronide and sulphate conjugates were studied in 10 patients following cholecystectomy.Total urinary excretion (0–24 h) was 36.6±16.4% of the 250 mg dose. Biliary excretion (0–24 h) was restricted to the phenolic and acyl glucuronides and accounted for 3.7±2.3% of the dose. An inverse relationship existed between urinary and biliary excretion of diflunisal and its conjugates.The data indicate that the reduced plasma clearance of diflunisal in patients with renal failure may, at least in part, be due to increased biliary excretion of diflunisal glucuronides followed by hydrolysis in the gut and reabsorption of diflunisal i.e. enterohepatic cycling.     

经皮肝穿刺胆道引流术治疗恶性梗阻性黄疸的护理

目的 探讨经皮肝穿刺胆道引流术（PTBD）治疗恶性梗阻性黄疸的护理策略.方法 对22例恶性梗阻性黄疸患者采取PTBD,术前、术中、术后进行严密的观察和护理.结果 22例患者均成功完成手术.通过及时的观察和针对性的有效护理,减少了患者术后并发症的发生,使患者治疗后获得更好的生活质量和更长的生存时间.本组患者没有出现死亡及其他严重并发症.结论 护理干预是保证患者配合手术,缩短手术时间,避免和减少术后并发症不可缺少的.     

Low‐dose probenecid selectively inhibits urinary excretion of phenolsulfonphthalein in rats without affecting biliary excretion

Renal organic anion transport systems play an important role in the excretion of anionic drugs and toxic compounds. Probenecid has been used as a potent inhibitor of urinary and biliary excretion of anionic compounds mediated by transporters such as organic anion transporters and multidrug resistance‐associated protein 2 (Mrp2). The purpose of this study was to optimize the dose of probenecid required for selective inhibition of urinary excretion of anionic compounds in rats, without inhibition of biliary excretion. Phenolsulfonphthalein (PSP), a model anionic compound that is excreted in urine and bile, was intravenously administered to rats after intraperitoneal injection of different doses of probenecid (0, 0.2, 2, 10, 100, 200 and 400 mg kg^?1). Treatment with 100, 200 or 400 mg kg^?1 probenecid decreased both renal clearance (CL_r) and biliary clearance (CL_b) of PSP, whereas 0.2 mg kg^?1 probenecid did not have any effect. Probenecid administered at doses of 2 and 10 mg kg^?1 decreased only CL_r. The median effective doses of probenecid for inhibiting CL_r and CL_b were 0.925 and 23.9 mg kg^?1, respectively. These data suggest that a low dose of probenecid selectively inhibits urinary excretion of PSP that may be mediated by organic anion transporters, without affecting biliary excretion that may be mediated by Mrp2. Copyright © 2011 John Wiley & Sons, Ltd.     

Minimal biliary excretion and enterohepatic recirculation of metoclopramide in patients with extrahepatic cholestasis

Summary The biliary excretion and apparent oral clearance of metoclopramide (MCL) were determined after oral administration of 1 mg MCL/kg body weight to 10 patients suffering from extrahepatic cholestasis with nasobiliary tube for drainage of the common bile duct. A bilioduodenal endoprosthesis was subsequently fitted in 6 of these patients, i.e. the enterohepatic circulation was restored, and the apparent oral clearance was re-determined.Biliary excretion, comprising free MCL and the products of conjugation, accounted for less than 1% of the administered dose. In accordance with this, the median areas under the plasma concentration-time-curves AUC(0–15 h) in patients with intact and interrupted enterohepatic recirculation were of similar size. The pharmacokinetic values in patients with cholestasis (median apparent oral clearance 0.5 l·kg^–1·h^–1; median t_1/2 4.5 h) were similar to those previously reported in patients with healthy liver function.We conclude that it is not necessary to adjust single doses of MCL in patients recovering from obstructive jaundice.     

Excretion of methylproscillaridin in patients with a biliary fistula

Summary Four patients with a biliary fistula received 0.5 mg³H-methylproscillaridin as a single oral dose. 55% of the dose was excreted in bile, 16% in urine and 3% in faeces. More than 60% of the radioactivity excreted in bile and urine appeared within the first 24 hours. 78% of the radioactivity in bile consisted of CHCl₃-insoluble metabolites of methylproscillaridin, incubation of which with -glucuronidase led to splitting off glucuronic acid from almost 80%. Methylproscillaridin can be regarded as the principal conjugated compound. TLC-separation of CHCl₃-soluble compounds from bile showed identical running of radioactivity with methylproscillaridin, proscillaridin and scillarenin and three unknown metabolites P₁, P₂, and P₃. In urine the CHCl₃-soluble fraction averaged 16% to 34% of the total amount and was identified as methylproscillaridin, proscillaridin, scillarenin, P₂ and P₃. The relative composition of the total radioactivity in faeces amounted to 77% methyl-proscillardidin, 4% scillarenin and 12% polar metabolites.     

Determination of the biliary excretion of piperacillin in humans using a novel method

AIM: To evaluate the applicability of a novel method to determine the biliary excretion of piperacillin. METHODS: Healthy volunteers were administered piperacillin i.v. Duodenal aspirates were collected via a custom-made oroenteric catheter; blood and urine also were collected. Gallbladder ejection fraction (EF) was determined by gamma scintigraphy and pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS: The fraction of the piperacillin dose excreted unchanged into bile was 1.1 +/- 0.3% (biliary clearance corrected for EF was 0.032 +/- 0.008 ml min(-1) kg(-1)). CONCLUSIONS: This methodology can be used to determine reliably the biliary clearance of drugs that are excreted only marginally into bile. Normalization of biliary clearance for EF significantly reduces intersubject variability of this parameter.     

Change and significance of T-cell subsets and TNF-α in patients with advanced malignant obstructive jaundice treated by percutaneous transhepatic biliary external and internal drainage

The aim of this article was to study the influence of immunity function of advanced malignant obstructive jaundice (MOJ) treated by percutaneous transhepatic biliary external and internal drainage. Ninety-six cases of MOJ were divided into two groups according to the different ways of biliary drainage. Fifty-two external drainage tubes were placed in 41 cases of percutaneous transhepatic biliary external drainage group and 66 metal stents were placed in 55 cases of percutaneous transhepatic biliary internal drainage group. Liver function, serum TNF-α and cellular function were examined one day before operation and one week after operation and liver function was re-examined two weeks after operation, in order to observe the change and analyze the association among them and compare with the control group. All patients’ conditions were improved after operation. In the percutaneous transhepatic biliary external and internal drainage groups, the total level of bilirubin decreased from (343.54±105.56) μmol/L and (321.19±110.50) μmol/L to (290.56±103.46) μmol/L and (283.72±104.95) μmol/L after operation respectively, which were significantly lower than pre-operation (P<0.05), but there was no significant difference between the two groups (P>0.05). Serum alanine aminotransferase (ALT) of all patients one week after operation was significantly lower than that before operation. TNF-α in percutaneous transhepatic biliary external and internal groups decreased from (108.58±19.95) pg/mL, (109.98±16.24) pg/mL of pre-operation to (104.32±19.59) pg/mL, (83.92±13.43) pg/mL of post-operation respectively, there was notable improvement (P<0.01) in internal drainage group after operation. Patients’ serum CD4, CD3 and CD4/CD8 were notably increased, but CD8 was notably decreased (P<0.05). There was no difference in external drainage group (P>0.05). There was a significant difference between the two groups. Serum TNF-α and ALT had positive correlation. Percutaneous transhepatic biliary internal or external drainage was an effective and important method to treat MOJ. Patients’ immune function was weak when they suffered MOJ, but body’s cellular immune function can be notably improved after internal biliary drainage.     

Pharmacokinetics of biliary excretion in man. VI. Indocyanine green

Summary The pharmacokinetics of Indocyanine Green (ICG) has been studied in 15 patients given 0.5, 1.0 and 2.0 mg · kg^–1. The plasma disappearance and biliary excretion rate were measured in patients with tightly fitting catheters under slight negative pressure in order to achieve complete collection of bile. Recovery of unchanged ICG in bile over 18 h after the i.v. injection was 80% of the dose in all three dose groups.Plasma disappearance in all 3 groups was biphasic, showing an initial phase with a t_1/2 of 3–4 min and a secondary phase with a dose-dependent apparent t_1/2 of 67.6, 72.5 and 88.7 min, respectively. After 0.5 and 1.0 mg · kg^–1 the biliary excretion rate curves showed an ascending phase with a mean t_1/2 of 5 min and a descending phase with a mean t_1/2 of 72 min. It was inferred that the secondary component of the plasma-decay mainly reflected the biliary excretion rate. After 2.0 mg · kg^–1 in some patients the biliary excretion curve showed features of saturation; the t_1/2 of the descending phase ranged from 73 to 440 min, and the time of maximal excretion was increased from 1.3 to 2.7 h after injection, whilst the mean maximal excretion rate was in the same range as the excretion rate after the 1.0 mg · kg^–1 dose. The non-linear pharmacokinetics was only moderately reflected in the measured plasma disappearance patterns. Two compartment analysis of the plasma levels indicated a clearance of 230–260 ml · min^–1, whereas the clearance conventionally calculated from the initial t_1/2 was 475 ml · min^–1. The volume of the central compartment in 70 kg patients was 2.31, which is about the plasma volume. The fictive volume of distribution in the liver (V₂) was 70–90 l, indicating marked hepatic storage of ICG. This was probably due to the very low liver-to-plasma transport rate (k₂₁) of 0.006–0.10 min^–1. Thus, the biliary excretion of ICG can be quantified by 2-compartment pharmacokinetic analysis of plasma disappearance curves, including a secondary phase. The latter, slow component was apparent at very low plasma levels due to the marked hepatic storage, and it was also influenced by retention of small amounts of impurities or degradation products. Improved detectability of this phase cannot simply be obtained by increasing the dose, since at doses exceeding 1.0 mg · kg^–1 non-linear elimination may complicate the pharmacokinetic analysis.     

经皮肝穿刺不同胆道引流术治疗恶性阻塞性黄疸效果比较

目的评价经皮经肝穿刺胆道引流术(PTCD)在恶性阻塞性黄疸(MBOJ)患者中的临床应用价值。方法回顾性分析1995-03～2009-07收治的118例恶性阻塞性黄疸患者的临床资料。按照不同方式分为三组。A组:经X线引导下经皮肝穿刺胆道置管引流术(xPTCD)放置可膨胀性胆道金属内支架(EMS)组27例。B组:超声引导下经皮肝穿刺胆道置管引流术(uPTCD)组75例。C组:xPTCD、uPTCD及ERCP下行胆道塑料内支架引流术(ERBD)或胆道金属支架置入内引流术(EMBE)组16例。结果三组之间的疗效及术后生存率等方面无显著差异(P>0.05),但A组及C组术后并发症的发生率明显增高(P<0.01)。结论 PTCD、ERBD/EMBE是手术不能根治的MBOJ较为有效的姑息性治疗方法,uPTCD法并发症较少,在实时、方便、经济、易防护等方面更具优势。     

Possible involvement of P-glycoprotein in the biliary excretion of grepafloxacin

1. In the present study, we have examined the effects of the quinolones norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX), tosufloxacin (TFLX), lomefloxacin (LFLX), sparfloxacin (SPFX) and grepafloxacin (GPFX) on the efflux of doxorubicin from mouse leukaemia P388/ADR cells expressing P-glycoprotein. The relationship between their partition coefficients (hydrophobicity) and effluxing potencies was also elucidated. 2. Both TFLX and SPFX strongly increased the intracellular accumulation of doxorubicin (5 micromol/L) in P388/ADR cells, but had no effect on P388/S cells not expressing P-glycoprotein. The rank of order of the potency of the quinolones (TFLX > SPFX > GPFX > NFLX) was not related directly to their hydrophobicity. These results suggest that some quinolones can reverse anticancer drug resistance. 3. Because GPFX is more highly excreted into the bile than other known quinolones, the effects of doxorubicin (10 mg/kg) or the well-known inhibitors of P-glycoprotein, namely cyclosporine A (10 mg/kg) and erythromycin (100 mg/kg), on the biliary excretion of GPFX at steady state was studied in rats. 4. Doxorubicin, cyclosporine A and erythromycin significantly decreased the biliary clearance of GPFX. Cyclosporine A and erythromycin had a much stronger inhibitory effect on the biliary excretion of GPFX than doxorubicin. These results suggest the possibility that GPFX is, at least in part, excreted into the bile by a P-glycoprotein-mediated transport mechanism.     

反相高效液相色谱法测定血浆中氟氧头孢浓度

目的 :优选流动相组成 ,建立氟氧头孢 (flomoxef,Fmox)血药浓度测定方法。方法 :色谱柱HypersilC18,流速1.0mL·min-1。采用正交实验法 ,以甲醇、乙腈、三乙胺的配比及pH为因素 ,在 3个水平上用L9(34)表进行实验。结果 :最优流动相组成为甲醇 乙腈 水 三乙胺 (16∶6∶78∶0 .4 ) ,用磷酸调节 pH为2 .5。血药浓度线性范围 0 .2 5～ 10 0mg·L-1(r =0 .9997,n =5 ) ,血浆中最低检测浓度为 0 .12 5mg·L-1(S/N =3)。高、中、低 3种浓度平均回收率分别为 :(96 .7± 3.9) % ,(95 .8± 2 .5 ) %和 (93.6± 2 .1) % ,n =5。结论 :本方法简便 ,准确 ,重现性好 ,为氟氧头孢药动学研究提供了一种检测方法。     

Use of primary rat hepatocytes in the gel entrapment culture to predict in vivo biliary excretion

1. In vitro models have been widely used in characterizing the hepatobiliary elimination of compounds. However, the application of in vitro models is often limited by their imperfect simulation of in vivo situations. The current paper aims to introduce the gel entrapment culture of rat hepatocytes as an alternative method for measuring hepatobiliary transport, with the sandwich culture of rat hepatocytes set as the control.

2. First, the culture conditions of the gel-entrapped hepatocytes were modified to enhance hepatic transport function. When cultured under optimal conditions, i.e. the collagen concentration was set to 0.6?mg/mL and the regular Williams’ E medium was supplemented with epidermal growth factor, the hepatocytes maintained much higher hepatic transporter gene expression levels and transport activities than that in regular gel entrapment and sandwich culture.

3. Compared with the actual values in rats, the predicted intrinsic biliary clearance (CL_{bile,int,predicted}) of the 10 model compounds in the optimized gel entrapment culture showed a high correlation coefficient squared (R²) of 0.94, with the majority falling within the two-fold error range of the in vivo values, which was much better than the comparable sandwich culture.

4. All of these results indicate that the optimized gel entrapment culture of hepatocytes is a suitable approach for estimating in vivo biliary excretion.

     

超声引导经皮肝穿刺胆管置管引流术治疗恶性梗阻性黄疸的临床效果

目的 探讨采用超声引导经皮肝穿刺胆管置管引流术对恶性梗阻性黄疸进行治疗的临床效果.方法 随机选取本院2013年9月至2015年2月收治的恶性梗阻性黄疸患者40例,所有患者均接受超声引导下经皮肝穿刺胆管置管引流术,对患者治疗前后相关生化指标的变化情况进行观察记录,同时对超声引导在经皮肝穿刺胆管置管引流术中的应用进行分析.结果 所有患者均顺利完成穿刺,成功率为100％.本次研究中40例患者经治疗,其总胆红素[(249±135)μmol/L]、直接胆红素[(72±26)μmol/L]等相关生化指标同治疗前[(429±213)μmol/L、(151 ±81)μmol/L]相比明显降低,差异有统计学意义(P＜0.05).结论 在超声监控下实施穿刺,可保证手术的顺利进行,能够有效改善黄疸相关临床症状和生化指标水平,对于改善患者的生存质量具有十分积极的作用.     

经皮胆道支架置入与姑息性胆肠内引流对胰头癌所致梗阻性黄疸的疗效观察

目的：探讨经皮胆道支架置入（ PTCD）对胰头癌所致梗阻性黄疸的疗效。方法对该院74例胰头癌晚期患者的临床资料进行回顾性分析。比较PTCD和姑息性胆肠内引流的疗效。结果观察组和对照组术后2周肝功能均明显好转,胆道梗阻情况均明显改善,差异有显著统计学意义（均P＜0．05）。观察组患者术后2周肝功能明显好于对照组,差异有统计学意义（P＜0．05）;但两组胆道梗阻情况比较差异无统计学意义（P＞0．05）。两组患者术中均未发生死亡事件,两组患者皮肤黄疸、瘙痒情况均逐渐消退或缓解、减轻。观察组患者住院时间和术中出血量少于对照组,差异有统计学意义（P＜0．05）。两组患者并发症发生率比较,差异无统计学意义（18．42％ vs 13．89％,P＞0．05）。两组患者术后生存时间比较差异无统计学意义（9．28±6．51）月vs （8．96±5．28）月,P＞0．05。结论对病情严重、身体状况较差、失去手术切除机会的胰头癌患者采用PTCD途径支架置入,不仅可有效解除患者胆道梗阻症状,且方便、安全、创伤小。     

Biliary and urinary excretion of inorganic arsenic: monomethylarsonous acid as a major biliary metabolite in rats.

In rats exposed to arsenite (AsIII) or arsenate (AsV), the biliary excretion of arsenic depends completely on availability of hepatic glutathione, suggesting that both AsIII and AsV are transported into bile in thiol-reactive trivalent forms (Gyurasics et al. [1991], Biochem. Pharmacol. 42, 465-468). To test this hypothesis, the bile and urine of bile duct-cannulated rats injected with AsIII or AsV (50 micromol/kg, iv) were collected periodically for 2 h and analyzed for arsenic metabolites by HPLC-hydride generation-atomic fluorescence spectrometry. Arsenic was excreted predominantly into bile in AsIII-injected rats, but the urine was the main route of excretion in AsV-exposed rats. Injected AsIII was excreted in urine practically unchanged, whereas both AsV and AsIII appeared in urine after administration of AsV. Irrespective of the arsenical administered, the bile contained 2 main arsenic species, namely AsIII and a hitherto unidentified metabolite. Formation of this metabolite could be prevented by pretreatment of the rats with the methylation inhibitor periodate-oxidized adenosine, indicating that it is a methylated arsenic compound. This metabolite could be converted in vitro into monomethylarsonic acid (MMAsV) by oxidation, whereas synthetic MMAsV could be converted into the unknown metabolite by reduction. Consequently, this biliary metabolite of both AsIII and AsV is monomethylarsonous acid (MMAsIII), a long-hypothesized, but never identified, intermediate in the biotransformation of AsIII and AsV. Although MMAsIII is thought to be formed from an oxidized precursor, rats injected with MMAsV did not excrete MMAsIII. In summary, the inorganic arsenicals investigated are transported into bile exclusively in trivalent forms, namely as AsIII and MMAsIII, but are excreted in urine in both tri- and pentavalent forms. Identification of MMAsIII is signified by the fact that this metabolite is more toxic than AsIII and AsV and thus formation of MMAsIII represents toxification of inorganic arsenic.     

Activities of cefoxitin in vitro and in vivo: a study in patients with biliary tract infection undergoing percutaneous transhepatic biliary drainage

Activities of cefoxitin and the effect on killing of bacteria in bile from six patients undergoing percutaneous transhepatic biliary drainage were analyzed in relation to in vitro activities of the drug, with particular reference to the incubation time. The bacteriostatic and bactericidal activities of cefoxitin with short term (6 hr) incubation correlated well with the duration of the effective cefoxitin concentration and the decrease of viable bacteria in bile juice from the patients. These timed in vitro activities can be used as well as the conventional MIC and MBC with the prolonged incubation of 24 hr, in the deductive analysis of bacterial response in vivo.     

基于授权理论的健康教育路径在经皮肝Ⅰ期胆道造瘘取石术后带管出院患者中的应用

目的 探讨基于授权理论的健康教育路径在经皮肝Ⅰ期胆道造瘘取石术后带胆管出院患者中的干预效果。方法 采用目的抽样法。选取 2019年 1月至 12月在广州医科大学附属第一医院行B超引导下经皮肝Ⅰ期胆道造瘘取石手术且带胆管出院患者86例,根据患者入院时间先后分为对照组和试验组,各 43例。对照组男 14例、女 29例,年龄（53.50±12.35）岁;试验组男 16例、女 27例, 年龄（52.50±11.26）岁。对照组给予常规健康教育,试验组采用基于授权理论的健康教育路径干预。 采用自我护理能力测定量表、胆管自我管理行为调查表、患者满意度问卷测评两组患者自我护理能 力、胆管自我管理行为、满意度及出院1个月内留置胆管相关并发症发生情况。计量资料组间比较采 用独立样本t检验,计数资料组间比较采用χ2 检验。结果 干预后,试验组患者的自我护理能力总分为（124.74±4.09）分,明显高于对照组的（110.81±4.45）分,试验组患者的胆管自我管理水平、满意度评分分别为（5.28±0.91）、（95.80±2.37）分,高于对照组的（4.09±1.27）、（91.70±4.15）分,差异均有统计学意义（均P<0.05）。试验组患者出现胆管堵塞、非计划性拔管、胆道感染并发症的总发生率为9.3%（4/43）, 低于对照组的25.58%（11/43）,差异有统计学意义（P<0.05）。结论 在经皮肝Ⅰ期胆道造瘘取石术后带胆管出院患者中实施基于授权理论的健康教育路径,可降低胆管相关并发症的发生率,改善自我管理行为,提高就诊满意度。     

A high throughput in vitro mrp2 assay to predict in vivo biliary excretion

1. Prediction of biliary excretion is a challenge for drug discovery scientists due to the lack of in vitro assays. This study explores the possibility of establishing a simple assay to predict in vivo biliary excretion via the mrp2 transport system.

2. In vitro mrp2 activity was determined by measuring the ATP-dependent uptake of 5(6)-carboxy-2′,7′-dichlorofluorescein (CDCF) in canalicular plasma membrane vesicles (cLPM) from rat livers. The CDCF uptake was time- and concentration-dependent (K_m of 2.2?±?0.3 µM and V_max of 115?±?26 pmol/mg/min) and strongly inhibited by the mrp2 inhibitors, benzbromarone, MK-571, and cyclosporine A, with IC₅₀ values ≤ 1.1 µM.

3. Low inhibition of CDCF uptake by taurocholate (BSEP inhibitor; 57 µM) and digoxin (P-gp inhibitor; 101 µM) demonstrated assay specificity towards mrp2.

4. A highly significant correlation (r²?=?0.959) between the in vitro IC₅₀ values from the described mrp2 assay and in vivo biliary excretion in rats was observed using 10 literature compounds.

5. This study demonstrated, for the first time, that a high throughput assay could be established with the capability of predicting biliary excretion in the rat using CDCF as a substrate.

     

106例高龄急性重症胆管炎经皮肝穿刺胆道引流的疗效观察

目的：观察B超引导下经皮肝穿刺胆道引流术（PTCD）在高龄急性重症胆管炎中的治疗效果。方法：对我院收治的106例高龄急性重症胆管炎患者行PTCD,观察临床治疗效果。结果：106例均穿刺置管成功,全部获得有效胆管引流,引流24～48h后腹痛减轻,体温逐渐降至正常。术后胆道出血2例,胆漏1例,导管脱落1例,导管堵塞2例,无气胸、血胸等并发症及死亡病例。结论：对难以耐受手术的高龄急性重症胆管炎患者,PTCD是一种安全、可靠、微创、有效的治疗方法。