Further studies on nitrofurantoin excretion in dog hepatic bile

1. Results obtained with a dog donor-recipient model indicate that following intravenous administration of nitrofurantoin sodium, nitrofurantoin is subjected to enterohepatic cycling. At least one-third of the nitrofurantoin originally excreted in the donors' bile after a nitrofurantoin dose of 3 mg/kg is reabsorbed intestinally in the recipients within 3 hours.2. After intraduodenal administration of a nitrofurantoin suspension to dogs at doses ranging from 2 to 12 mg/kg, about 10% of the dose is recovered in bile as nitrofurantoin within 6 hours. A hydrocholeretic effect was also observed which correlated with the amount of drug administered. Both biliary drug excretion and the related hydrocholeresis appeared linearly related over the drug dose range.3. The hydrocholeresis observed in dogs within 3 h after intravenously administered nitrofurantoin sodium, equivalent to 3 mg/kg nitrofurantoin, was at least ten times that seen following the intravenous administration of an equimolar dose of dehydrocholic acid given as its sodium salt.     

Excretion of nitrates and nitrites in saliva and bile in the dog

The kinetics of salivary and biliary excretion of inorganic nitrates and nitrites was studied in mongrel dogs after iv injection of these compounds labelled with 15N. There was strong salivary excretion of 15NO-3 after injection of Na15NO3 but little or no nitrites were excreted in the saliva, indicating that the nitrites present in the mouth are mainly the result of in situ transformation of nitrates into nitrites. In the bile, large quantities of nitrates were excreted when the dogs received 15NO-2, indicating endogenous oxidation of the nitrite.     

Excretion of antibiotics in bile

The excretion of antibiotics in the bile of rats has been studied. Penicillins, including derivatives of 6-aminopenicillanic acid, are rapidly excreted, reabsorbed and re-excreted, in high concentration, whereas streptomycin, neomycin, paramomycin and chloramphenicol reach lower levels in the bile than in the plasma. p-Aminobenzylpenicillin and D(—)-6-(α-amino-α-phenylacetamido)penicillanic acid, both of which are bactericidal to Salmonellae and other coliforms, produce higher concentrations in the bile than benzylpenicillin (penicillin G). This may be of therapeutic importance.     

Excretion of hydroflumethiazide in bile and urine of man

Summary Biliary and urinary excretion of hydroflumethiazide (HFT) and its metabolite, 2,4-disulfamyl-5-trifluoromethylaniline (DTA), was investigated in 5 otherwise healthy patients with a T-drain in the common bile duct after cholecystectomy and choledochotomy. After a single oral dose of HFT 302–453 µmoles, a mean of 0.051% (range 0.028–0.075) of the dose was excreted in bile and 34.9% (range 23.7–45.4) in urine during the first 6 hours after administration. Biliary excretion appeared to be of minor importance in the elimination of HFT by man. DTA could not be detected in bile.     

Excretion and re-excretion of a broad-spectrum penicillin in bile

A technique is described for estimating the biliary excretion, reabsorption and re-excretion of an antibacterial drug in rats. D(—)-6-(α-Amino-α-phenylacetamido)-penicillanic acid (BRL 1341) is rapidly excreted and re-excreted in the bile, in concentrations bactericidal to Salmonellae and other organisms which are usually refractory to antibacterial drugs in this situation. Recoveries of the drug accounted for 20 to 30% of oral of parenteral doses; much of the remainder is probably destroyed in the gut. Results from one patient indicate that D(—)-6-(α-amino-α-phenylacetamido)-penicillanic acid is excreted in high concentration also in human bile.     

Excretion of nicotine and its metabolites in dog and monkey saliva

Salivary and plasma levels of unchanged nicotine and total radioactivities (nicotine and its metabolites) were determined sequentially at short time intervals following iv injection of ³H-labeled nicotine (100 μg/kg) to dogs and rhesus monkeys. Immediately after the drug injection, high concentrations of nicotine appeared in parotid and submandibular saliva induced by pilocarpine infusion or by auriculotemporal nerve stimulation. Excretory patterns of nicotine and total radioactivities in both glands were almost similar but were significantly different between the 2 species. Nicotine was excreted more readily in dog saliva than monkey. The salivary: plasma concentration ratios for nicotine were higher than those for total radioactivities in both species. Nicotine seems to be more readily excreted in saliva than its metabolites. The concentrations of nicotine and total radioactivities in saliva were independent of variation in salivary flow rate and were not affected by the method of stimulation. The chromatographic patterns of parotid and submandibular saliva resembled those of plasma in the same species. Chromatographic studies showed that most of the administered nicotine appeared in plasma and saliva in the form of cotinine 5–60 min after the injection. ³H-Nicotine: total ³H-radioactivity concentration ratios (³H-nicotine: total ³H) of both saliva and plasma in monkeys were lower than those in dogs. The times at which ³H-nicotine: total ³H ratio became 0.5 in plasma and saliva were very short (2–9 min); in addition, those in monkeys were short relative to dogs.     

Excretion of sulfobromophthalein in rats with iodomethane-induced depletion of hepatic glutathione

Summary Male urethane-anesthetized Wistar rats with biliary fistulas were infused for 60 min i.v. with sulfobromophthalein (BSP) or BSP-glutathione conjugate (BSP-GSH) at 594 nmol/100 g/min. Thirty minutes prior to the start of the infusion, 20 mg/kg iodomethane, dissolved in olive oil, was given into the duodenum. The control received oil only. At the start of the infusion the hepatic concentration of GSH was 0.96±0.23 mg/g liver in the iodomethanetreated animals versus 1.93±0.13 mg/g liver in the control (P<0.001).When unconjugated BSP was infused, the excretion of total BSP (unconjugated plus conjugated) was markedly lower in the iodomethane-treated group than in the control. This difference was due solely to differences in biliary appearing conjugated BSP; the excretion of unconjugated BSP was identical in both groups. The different excretion patterns were paralleled by equal hepatic accumulation of total BSP in both groups. The ratio of unconjugated BSP/BSP-GSH in the liver was about twice as high after pretreatment with iodomethane than in the control group.When BSP-GSH instead of BSP was infused, the excretion rates of this dye were identical in both groups. The maximal transport capacity (T_m) was double that observed with infusion of unconjugated BSP in control animals. There is indirect evidence that BSP and BSP-GSH might have different excretion pathways.     

Cefmetazole excretion into the bile after hepatic portojejunostomy in congenital bile duct atresia

Antibiotics excretion into the bile was studied using CMZ which was administered by drip infusion in 12 postoperative cases of congenital bile duct atresia patients who had hepatic portojejunostomy with SURUGA II type enterostomy with the following results. Group I (correctable type children, with good bile flow, no jaundice): Excellent excretion was almost the same as that seen in adult patients. Group IIa (uncorrectable type children, with good bile flow, no jaundice): Excretion was poor but good depending on the amount of bile flow and liver function. Group IIb (uncorrectable type children, with poor bile flow, jaundice): Excretion was very poor. Group III (uncorrectable type infants, with good flow, no jaundice): Excretion was good depending on the amount of bile flow and liver function. Our study indicates that antibiotics excretion into the bile in children is closely related to the condition of the hepatic function and biliary passage.     

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Aim:

To evaluate the antifibrotic effect of telmisartan, an angiotensin II receptor blocker, in bile duct-ligated rats.

Methods:

Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats, model rats underwent common bile duct ligation (BDL), and BDL rats treated with telmisartan (8 mg/kg, po, for 4 weeks). The animals were sacrificed on d 29, and liver histology was examined, the Knodell and Ishak scores were assigned, and the expression of angiotensin-converting enzyme (ACE) and ACE2 was evaluated with immunohistochemical staining. The mRNAs and proteins associated with liver fibrosis were evaluated using RTQ-PCR and Western blot, respectively.

Results:

The mean fibrosis score of BDL rats treated with telmisartan was significantly lower than that of the model rats (1.66±0.87 vs 2.13±0.35, P=0.015). However, there was no significant difference in inflammation between the two groups, both of which showed moderate inflammation. Histologically, treatment with telmisartan significantly ameliorated BDL-caused the hepatic fibrosis. Treatment with telmisartan significantly upregulated the mRNA levels of ACE2 and MAS, and decreased the mRNA levels of ACE, angiotensin II type 1 receptor (AT1-R), collagen type III, and transforming growth factor β1 (TGF-β1). Moreover, treatment with telmisartan significantly increased the expression levels of ACE2 and MAS proteins, and inhibited the expression levels of ACE and AT1-R protein.

Conclusion:

Telmisartan attenuates liver fibrosis in bile duct-ligated rats via increasing ACE2 expression level.     

Excretion and biotransformation of carboxymethyl-cysteine in rat, dog, monkey and man.

1. Following an oral dose of S-carboxymethyl [35S]cysteine monkey (rhesus and African green), rat, dog, and man excreted 77,88,95, and 100% respectively of the 35S radioactivity in urine and 7.0, 2.5, 0.7, and 0.3% in faeces during a 3 to 4 day period. 2. The principal drug-related components excreted were unchanged carboxymethylcysteine, dicarboxymethyl sulphide and inorganic sulphate. 3. Rat, dog, and man excreted primarily dicarboxymethyl sulphide and unchanged carboxymethylcysteine and no inorganic sulphate (rat, 7%). 4. Monkey excreted largely inorganic sulphate, moderate amounts of dicarboxymethyl sulphide and a trace of unchanged drug.     

腹腔镜左肝外叶切除术治疗肝胆管结石的临床效果

目的：探讨腹腔镜左肝外叶切除术治疗肝胆管结石的临床效果。方法选取本院2010年1月~2014年9月收治的38例肝胆管结石患者为研究对象,按不同手术方法分为治疗组和对照组,对照组采用开腹左肝叶切除术,治疗组采用腹腔镜左肝叶切除术,对比两组患者的术中出血量、手术时间、术后住院时间、红细胞输注数量以及并发症发生情况。结果治疗组术中出血量和红细胞输注数量少于对照组,手术时间短于对照组,差异有统计学意义（P<0.05）。两组患者并发症发生率差异无统计学意义（P>0.05）。结论应用腹腔镜左肝外叶切除术治疗肝胆管结石具有出血量少、红细胞输注数量少的特点,对患者造成的创伤较小,值得临床推广应用。     

肝内胆管结石合并肝门部胆管狭窄的手术处理分析

目的探讨肝内胆管结石并肝门部胆管狭窄的手术方法。方法回顾性分析我院47例肝内胆管结石并肝门部胆管狭窄手术治疗的临床资料,遵循“清除结石,解除狭窄,切除病肝,通畅引流”的原则,我们采取病肝切除、术中胆道镜检查、取石,肝门部胆管狭窄整形,胆肠R oux-en-Y大盆口吻合,空肠盲袢皮下埋置等综合治疗。术后常规消炎利胆片或中医中药预防结石复发。结果治愈45例(95.7%)。术前黄疸深重,术中渗血不止,停止手术,死亡1例,术后46天胃瘫并衰竭死亡1例。术后发现残留结石4例(8.7%),结石复发3例(6.5%),优良率93.7%;术后并发胆汁漏3例(6.5%),残留结石术后6周经T管窦道取净结石4例。结石复发的3例中经切开皮下空肠盲袢纤维胆道镜取石成功1例,再手术切除狭窄胆肠吻合口,重新行胆管空肠吻合,并应用纤维胆道镜取石2例。结论术前完善的检查对于了解肝内胆管结石的分布及肝门部胆管狭窄的范围有着重要的意义并能为手术方案的制订提供积极的指导作用。病变肝叶或肝段切除、肝门部狭窄胆管大范围切开整形、术中应用纤维胆道镜检查、取石、并建立皮下便捷通道的肝胆管空肠R oux-en-Y大盆口吻合是治疗该疾病的首选综合治疗方法。术后常规用药预防结石复发也是必要的。     

All-trans retinoic acid regulates hepatic bile acid homeostasis

Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract.     

Inhibition of hepatic uptake of bile acids by rifamycins

Summary The effect of rifamycin SV and rifampicin on hepatic bile acid uptake was studied using isolated rat hepatocytes in presence and in absence of albumin. The drugs inhibited cholate uptake more than taurocholate uptake and the inhibition was of non-competitive type. In presence of 3% albumin the inhibitory effect of the drugs was more for cholate and less for taurocholate uptake than in absence of albumin. Neither the binding of bile acids nor that of the drugs to albumin was altered by one another. Thus the effect in presence of albumin cannot be explained by the binding of the drugs and bile acids to albumin alone. It is suggested that albumin interacts with hepatic bile acid uptake process and this interaction with cholate uptake is different from that with taurocholate uptake. This additional and different effect of albumin may explain the effect of the drugs in presence of albumin. The results may be of clinical significance in rifamycins treatments.Part of this publication was presented in the 18th Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft (1977)