Biliary excretion and enterohepatic cycling of glycyrrhizin in rats

The enterohepatic cycling of glycyrrhizin was examined using rats with and without biliary fistulization. The plasma decay in the control rats without fistulization following an iv dose of 100 mg/kg of glycyrrhizin, was generally biphasic. However, secondary peaks were observed in all rats in the elimination phase, i.e., 0.5 to 12 h following dosing. The plasma concentrations in the rats with biliary fistulization administered the same dose showed a biexponential decline. The AUC and CLtot were significantly higher and lower in the control rats, respectively. The biliary excretion was 80.6 +/- 9.9% of the administered dose, and intestinal absorption was confirmed by using the bile collected after iv dosing. From these results, we concluded that glycyrrhizin was predominantly secreted from the liver into the bile, and that the secondary peaks in the elimination phase, the higher AUC, and the lower CLtot in the control rats were due to the effects of enterohepatic recycling of glycyrrhizin. Furthermore, the transport of the drug from the liver to the bile appears to be a saturable process.     

Alterations in biliary excretory function by streptozotocin-induced diabetes

Hepatic clearance and biliary excretion of model substrates for each of four carrier-mediated transport systems were studied in male Sprague-Dawley rats treated 28 days earlier with 45 mg/kg streptozotocin iv to induce uncontrolled insulin-deficient diabetes. Diabetic rats exhibited hyperglycemia (560 mg/dl), polyuria (160 ml/24 hr), polyphagia, polydipsia, and generalized myopathy. The plasma disappearance, biliary excretion, and elimination half-life of the anionic dye phenol red was unchanged in diabetic rats, but total clearance of phenol red was increased. Conjugation of phenol red with glucuronic acid appeared to be increased in diabetic rats, whereas acetylation of procainamide ethobromide was decreased. Plasma elimination and total clearance of cationic procainamide ethobromide, uncharged ouabain, and the bile acid taurocholate were significantly increased in diabetic animals. Biliary excretion of these three compounds was only slightly elevated in the first 15 min after administration and was decreased after 1 hr. Biliary and total systemic clearance were also increased from 2-3-fold for procainamide ethobromide, ouabain, and taurocholate. These changes in clearance are predominantly due to the 2-5-fold increase in steady state volume of distribution. Basal bile flow rates were increased by 62% after the induction of diabetes to 88 microliter/min/kg. Diabetic rats secreted higher levels of bile acids, cholesterol, and phospholipids into bile. These data indicate that long term insulin-dependent diabetes does alter hepatic excretory function.     

Induction of multidrug resistance-associated protein 2 in liver, intestine and kidney of streptozotocin-induced diabetic rats

Many studies have demonstrated that Mrp2 is highly regulated in some physiopathological situations. The aim of this study was to investigate effects of diabetes mellitus on function and expression of multidrug resistance-associated protein 2 (Mrp2) in rat liver, kidney and intestine. Diabetic rats were induced by an intraperitoneal administration of streptozotocin (65?mg/kg) and randomly divided into diabetic (DM) rats and insulin-treated diabetic rats. Sulfobromophthalein (BSP), a substrate of Mrp2, was used to evaluate Mrp2 function in vivo. Data from excretion experiments demonstrated that compared with normal rats, diabetes markedly enhanced BSP excretion via bile, urine and intestinal perfusate, which contributed to the elevated plasma clearance of BSP after intravenous administration of 45 μmol/kg BSP. Western blot results showed higher levels of hepatic, renal and intestinal Mrp2 protein in DM rats, although no difference was observed in renal Mrp2. Insulin treatment partly reversed these alterations. Induction of Mrp2 by diabetes was in parallel with the increase in bile flow, levels of biliary and plasma total bile acid (TBA), and plasma conjugated bilirubin in DM rats. Diabetes may enhance Mrp2 function and expression in liver, kidney and intestine, which might be due to insulin deficiency, increased TBA and conjugated bilirubin.     

Influence of Pentobarbitone on In-vivo Local Disposition of Diclofenac in Rat Liver

Because the liver is the main organ eliminating many drugs from the body and because pentobarbitone and other analogues can inhibit biliary secretion, the influence of pentobarbitone on hepatic local disposition of diclofenac has been investigated. Diclofenac was infused into the portal and femoral veins of non-anaesthetized rats (group A) and rats anaesthetized with pentobarbitone (group B) and the plasma concentration of diclofenac and the total amount of diclofenac excreted in the bile (in both cases intact diclofenac plus its glucuronide) were simultaneously monitored by HPLC at appropriate time intervals. The time-courses of plasma concentration and amount excreted in the bile were evaluated by moment analysis with trapezoidal integration. The hepatic recovery ratio (F_H) was calculated by comparing the area under the curve (AUC) of plasma concentration after intravenous infusion with that after intraportal infusion. The mean biliary transit time (t_b) was estimated by subtracting the mean residence time (MRT) of the plasma data from the mean biliary residence time (MRT_b) of the biliary excretion data. The F_H values of diclofenac were 0.664 in group A and 0.643 in group B. The biliary excretion ratio (F_b) of total diclofenac after intravenous administration was 27.0% in group A and 14.1% in group B. The t?_b values for total diclofenac were estimated to be 0.192 h (intravenous) and 0.159 h (intraportal) in group A, and 0.174 h and 0.238 in group B. Analysis of variance showed that differences among these four t?_b values were insignificant at the 5% level. The differences in the mean residence time (MRT), total clearance (CL) and distribution volume at steady state (V_SS) were insignificant between groups A and B. Whereas total and the hepatic clearance of diclofenac were not affected by pentobarbitone, biliary clearance was extensively reduced. It took a relatively long time for diclofenac to move from the sinusoid into the bile and the time was not affected by pentobarbitone.     

EFFECTS OF DIABETES ON DISPOSITION AND HEPATIC HANDLING OF CEFMETAZOLE IN RATS

1. The effects of streptozotocin-induced diabetes on disposition and hepatic handling of cefmetazole, a broad-spectrum cephalosporin, were investigated in rats. 2. Male Wistar rats were pretreated with streptozotocin (60 mg/kg, i.p.) to induce uncontrolled diabetes. Fourteen days later bile flow was significantly reduced (12%) and bile acid secretion was significantly enhanced (87%) when compared with control animals. 3. Following intravenous injection of cefmetazole at a dose of 200 μmol/kg, maximal and cumulative biliary excretion of the antibiotic were significantly impaired in streptozotocin-treated animals (27 and 22%, respectively). 4. Cefmetazole excretion into bile was accompanied by marked choleresis. The magnitude of bile flow increase was larger in control animals. 5. Total systemic clearance of the antibiotic was reduced (36%) and mean half-life for the fast and slow phases of disposition increased (136 and 48%, respectively) in diabetic rats. 6. These changes were probably due to the diabetic condition of the animals because insulin treatment resulted in almost complete cofrection.     

Effect of chlorpromazine on hepatic transport of indocyanine green in rats

The effect of chlorpromazine hydrochloride (CPZ) on the hepatic transport of indocyanine green (ICG) was studied in the rat, in an attempt to elucidate the mechanisms of hepatotoxicity of CPZ in vivo, by comparing the pharmacokinetic parameters of ICG after bolus and chronic administration of CPZ. Delays were shown in both plasma disappearance and biliary excretion of ICG in the CPZ-treated rats (10 and 15 mg/kg intraportal bolus administration). Significant decreases were observed in the pharmacokinetic parameters, V₂ and total body clearance (CL_tot) in CPZ 10 mg/kg treated rats and k₃₄, V₂ and CL_tot in CPZ 15 mg/kg treated rats, while a significant increase was observed in k₂₁ in both CPZ-treated groups; V₁ was not altered. The apparent liver-to-plasma concentration ratio (K_p,app) of ICG at 50 min after i.v. administration was decreased significantly in CPZ 15 mg/kg treated rats when compared to control rats, suggesting an alteration in the distribution of ICG to the liver by CPZ. Bile flow rates decreased immediately after bolus intraportal administration of CPZ in both CPZ-treated groups, and they then returned progressively to the basal levels. The output of bile acids was also inhibited by CPZ in a time-dependent and reversible manner and the bile acid independent fraction of bile flow was decreased significantly in both CPZ-treated groups. Chronic treatment with CPZ (10 or 20 mg/kg, i.p., per day for 3 weeks) did not alter either the pharmacokinetic parameters or the bile secretion profile of ICG, although there were significant decreases in body and liver weights in CPZ-treated groups. This may have been due to the rapid metabolism and excretion of CPZ in the rat when compared to humans. It is proposed that the acute toxic effect of CPZ on hepatic transport of ICG in the rat may be due mainly to the time-dependent and reversible cholestasis induced by CPZ, and that chronic treatment with CPZ may not alter the hepatic transport of ICG in the rat.     

Pharmacokinetics of valproic acid in guinea-pigs with biliary abnormality.

To explore whether biliary cannulation, biliary obstruction or gall bladder obstruction could alter the disposition of valproic acid, guinea-pigs were subjected to common bile duct cannulation or ligation, gall bladder-neck ligation or sham surgery as a control. They were then given an intravenous (i.v.) dose of sodium valproate (50 mg kg-1) and the pharmacokinetics of valproic acid in each group were compared. In the cannulated group, significant decreases (P less than 0.05) in the area under the elimination curve (AUC), the volume of distribution at steady-state (Vdss) and the mean residence time (MRT) were observed. Significant increases (P less than 0.05) in the elimination rate constant (kz) and total clearance (CLtot) of valproic acid were noted. In the biliary obstructed guinea-pigs, the Vdss was significantly decreased (P less than 0.05). In the gall bladder obstructed guinea-pigs, there was a secondary peak of valproate plasma concentration, and the kz was significantly decreased. The biliary excretion of unchanged and conjugated valproic acid was 2.0 +/- 0.7 (s.e.m.) and 19.7 +/- 3.6 (s.e.m.)% of dose, respectively, and was almost completely reabsorbed in the enterohepatic recycling. Urinary excretion of unchanged and conjugated valproic acid, as well as non-conjugate metabolic clearance of valproic acid, were not significantly different among the four groups. The results suggest that the pharmacokinetics of valproic acid in guinea-pigs are particularly sensitive to interruption of the enterohepatic cycle. Biliary obstruction may elevate plasma concentrations owing to the decreased Vdss of valproic acid. Gall bladder obstruction may cause fluctuation of valproate plasma concentrations. The data indicate that the apparent total clearance of valproic acid is significantly less than the intrinsic clearance owing to enterohepatic recycling.     

Involvement of multiple transport systems in the disposition of an active metabolite of a prodrug-type new quinolone antibiotic, prulifloxacin

Prulifloxacin is a prodrug-type new quinolone. The purpose of this study is to clarify the mechanism of biliary excretion and brain distribution of its active metabolite, UFX. UFX was efficiently excreted into the bile in rats, with its concentration in the bile being 30-60 times higher than that in plasma. The in vivo disposition study revealed that multidrug resistance-associated protein 2 (MRP2) was involved in the biliary excretion of glucuronide metabolite, but not of the unchanged UFX. A transport study using a P-glycoprotein (P-gp) overexpressing cell line, LLC-GA5-COL150, showed that UFX was a substrate of P-gp. Nevertheless, the biliary clearance (CLbile) of UFX in P-gp-gene-deficient mice was not different from that in the normal mice, although the concentration in the liver was slightly higher than that in the normal mice. These observations suggest that multiple transport systems are involved in the biliary excretion of UFX, with minor contribution of P-gp. The distribution of UFX in the rat brain was quite low, and its tissue to plasma concentration ratio (Kp) in the brain was much less than the unity and was increased by cyclosporin A. The Kp in the brain of mdr1a/1b(-/-) mice was higher than that in the normal mice, suggesting that efflux by P-gp played a major role in the limited brain distribution of UFX.     

The effects of probenecid on the excretion kinetics of stanozolol, an anabolic steroid, in rats.

The pharmacokinetic behaviour and the mechanism of renal excretion of stanozolol (STZ), as affected by co-treatment with probenecid, were studied in male Sprague-Dawley rats. Pharmacokinetic parameters following intravenous (i.v.) administration of STZ (20 mg kg-1 body wt.) were measured in both STZ-treated (control) and STZ plus probenecid-treated (treatment) groups. In order to assess the renal clearance of STZ, bolus doses of STZ and inulin (40 mg kg-1 body wt.) were injected i.v. either in the presence or absence of probenecid (40 mg kg-1 body wt.). The blood and urine concentrations of STZ were determined by capillary gas chromatography-mass spectrometry (GC-MS). In the probenecid treatment group, the area under the plasma disappearance and urinary excretion curves (AUC) of STZ were significantly decreased (P < 0.01) and the volume of distribution (Vd) and total clearance (CLt) were significantly increased statistically (P < 0.05 and P < 0.01, respectively). No remarkable differences in the urine flow rate, urine pH values, glomerular filtration rate (GFR) or renal clearance were observed in the treatment group. However, the clearance ratio in the treatment group was significantly increased from 11.72 to 17.27. From these results, it is suggested that the significant decrease of AUC, i.e. increase of disappearance of STZ in plasma by co-administration with probenecid, is due to the increase of the clearance ratio.     

Pharmacokinetic aspects of sulfobromophthalein transport after diethyl maleate pretreatment in rats

The pharmacokinetics of sulfobromophthalein was studied in the rat after depletion of hepatic glutathione levels induced by intraperitoneal administration of diethyl maleate (4.0 mmol/kg). After an intravenous bolus injection of sulphobromophthalein (120 mumol/kg) a biexponential plasma decay was found both in control and diethyl maleate pretreated rats. The initial plasma clearance Cl12 was not modified by diethyl maleate administration. The rate constant of biliary excretion K23 was significantly lowered in diethyl maleate pretreated rats, which could by explained by the change in the biliary excretory process. The cumulative biliary excretion of sulphobromophthalein was decreased by about 50% following diethyl maleate injection, with a reduction of the percentage of conjugated dye excreted into bile.     

The effects of biliary obstruction on excretion of cefoperazone in the rat

A study has been carried out on the influence of biliary obstruction on the elimination of cefoperazone (CPZ), an antibiotic mainly excreted in the bile. Rats were submitted to ligature of the common bile duct, given CPZ 100 mg/kg i.m., and killed 1 to 72 h afterwards. At death, measurements were made of CPZ concentrations in the serum, liver, lung, striated muscle, kidney, urine, intestinal wall and intestinal contents. The results were compared with those found in intact and in sham operated rats. Biliary obstruction led to a prolongation of the time taken for CPZ to disappear from the serum and markedly changed the way in which the drug was excreted. The amount of the drug excreted in the urine was 88% in the presence of biliary obstruction compared with 6% in intact rats and 14% in sham operated rats. The amount of CPZ in the small intestine 1 h after injection was very high in sham operated rats but only minimal amounts were found at this time in the presence of biliary obstruction. However, from 6 h after the injection, large amounts of CPZ were found in the intestinal contents despite the presence of biliary obstruction. In conclusion, in the presence of biliary obstruction, CPZ is eliminated by a combination of urinary and intestinal (non-biliary) excretion.     

Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats.

The relationship between biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats was examined. The biliary excretion of seven model substrates in 96-h sandwich-cultured rat hepatocytes was determined by differential cumulative uptake of substrate in the monolayers preincubated in standard buffer (intact bile canaliculi) and Ca2+-free buffer (disrupted bile canaliculi). Biliary excretion in vivo was quantitated in bile duct-cannulated rats. The biliary excretion index of model substrates, equivalent to the percentage of retained substrate in the canalicular networks, was consistent with the percentage of the dose excreted in bile from in vivo experiments. The in vitro biliary clearance of inulin, salicylate, methotrexate, [D-pen2,5]enkephalin, and taurocholate, calculated as the ratio of the amount excreted into the bile canalicular networks and the area under the incubation medium concentration-time profile ( approximately 0, approximately 0, 4.1 +/- 1.0, 12.6 +/- 2.2, and 56. 2 +/- 6.0 ml/min/kg, respectively), correlated with their intrinsic in vivo biliary clearance (0.04, 0, 17.3, 34.4, and 116.9 ml/min/kg, respectively; r2 = 0.99). The model compound 264W94 was not excreted in bile either in vivo or in vitro. The glucuronide conjugate of 2169W94, the O-demethylated metabolite of 264W94, was excreted into bile in vitro when 2169W94, but not 264W94, was incubated with the monolayers; 2169W94 glucuronide undergoes extensive biliary excretion after administration of 264W94 or 2169W94 in vivo. Biliary excretion in long-term sandwich-cultured rat hepatocytes correlates with in vivo biliary excretion. The study of biliary excretion of metabolites in the hepatocyte monolayers requires consideration of the status of metabolic activities.     

Non-micelle forming bile acids increase biliary gentamicin excretion in the rat

To investigate whether non-micelle forming bile acids are able to increase biliary gentamicin excretion, male Sprague-Dawley rats were anesthetized with pentobarbital and fitted with a biliary fistula. After a control period of 30 min, dehydrocholate, taurodehydrocholate, or norursodeoxycholate were administered iv at doses of 2 or 10 mumol.min-1.kg-1. Taurodehydrocholate increased bile flow and biliary gentamicin clearance similarly in a dose-dependent fashion. Its unconjugated analogue, in contrast, increased gentamicin clearance fourfold, while increasing bile flow only 1.6-fold. This suggests that other than purely osmotic phenomena were involved. This effect was even more marked for the short-chain bile acid, norursodeoxycholate. At a dose of 2 mumol.min-1.kg-1 it increased bile flow by 30%, but gentamicin clearance by 210%; a similar discrepancy between choleresis and gentamicin clearance was observed at the higher dose tested. It may be concluded that conjugated triketo bile acids increase biliary gentamicin clearance by osmotic choleresis. Unconjugated triketo bile acids and nor-bile acids, to an even greater extent, increase gentamicin clearance much more markedly than bile flow; other effects, such as the putative cholahepatic shunt pathway, are responsible for this phenomenon. This novel therapeutic principle might be useful in achieving therapeutic biliary antibiotic concentrations or in treating gentamicin intoxication in patients with renal insufficiency.     

The effect of therapeutic doses of paracetamol on liver function in the rat perfused liver

Abstract— The isolated liver perfusion technique was used to study the effect of therapeutic doses of paracetamol on hepatic gluconeogenesis and bromosulphthalein clearance from the perfusate and biliary excretion of the dye in the rat. Six groups of rats were studied; those in the three experimental groups were given 0·02 g kg^?1 paracetamol daily for ninety days. The livers of animals in the control group and in one of the experimental groups were perfused with a medium containing pyruvate. The animals in the second experimental and control group were perfused with a medium containing bromosulphthalein (10 mg/100 mL). The livers of the third experimental and control group were subjected to histological examination. The rate of glucose formation and glucose concentrations were decreased, while, lactate levels and lactate: pyruvate ratios were increased in paracetamol-treated rats. The mean concentration of bromosulphthalein in the perfusate and biliary excretion of the dye were decreased. Macro and micro vesicular fatty change was present in the livers of paracetamol-treated rats. This study demonstrates that chronic administration of therapeutic doses of paracetamol to rats adversely affects liver function, as evidenced by impaired gluconeogenesis and bromosulphthalein clearance from the perfusate, and excretion of the dye into the bile, and provides histological evidence of hepatic damage in rats.     

Excretion of antibiotics into bile and urine in patients with external cholecystostomy done in order to treat obstructive jaundice

Biliary and urinary concentrations and recoveries of 3 different antibiotics (piperacillin (PIPC), cefbuperazone (CBPZ) and cefoperazone (CPZ], after intravenous bolus injection were studied using the crossover method with external cholecystostomies done in order to treat obstructive jaundice due to complete obstruction of the lower biliary tract; the concentrations of antibiotics in bile and urine were determined by means of a high performance liquid chromatography method. Drug concentrations and recoveries in the bile after intravenous injection of these antibiotics were at levels in the order of CPZ greater than CBPZ greater than PIPC. Since our patients were inflicted with various malignancies which made them impaired in terms of biliary excretion of antibiotics, the concentrations of those drugs in the bile were lower than those previously reported by several investigators. However, CBPZ and CPZ showed sufficient levels of excretion into the bile and their amounts were high enough when compared to the value of MIC 80% reported recently against Escherichia coli and Klebsiella pneumoniae, which are known to be main pathogens of biliary system infections. The excretion of CPZ into the bile was invariably found to be 2 times or more as high as the other 2 drugs tested. Concentrations and recoveries of the 3 antibiotics excreted into urine were similar to the cefotaxime excretion, of which into urine had been reported to be excellent. Thus, CBPZ and CPZ appeared to be effective against biliary system infections, even with blockage of antibiotics excretion into the bile.     

Effects of Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) on intestinal function in streptozotocin-induced diabetic rats

We examined the effects of Hachimi-jio-gan (HJ) on the small intestinal function in streptozotocin (STZ)-induced diabetic rats. The rats had free access to pellets containing 1% HJ extract powder for 4 weeks after STZ administration. The intestinal disaccharidase (sucrase and maltase) activity was elevated in STZ-treated rats compared with control rats, whereas it was significantly reduced by HJ administration. This suggested that HJ suppresses or delays monosaccharide production in the small intestinal epithelium. In addition, the intestinal mucosal weights and DNA contents that were significantly increased in the STZ-treated rats were restrained to the control level by HJ treatment. Simultaneously, we examined the changes in the plasma levels of glucagon-like peptide 2 (GLP-2), which is a trophic factor specific for the intestine. The plasma GLP-2 levels significantly increased in the STZ-treated rats, whereas HJ decreased the plasma GLP-2 levels. Thus intestinal mucosal weights and DNA contents correlated with plasma GLP-2 levels in diabetes-associated bowel growth. These results suggest that HJ may normalize or suppress the small intestinal disaccharidase activity and the epithelial cell proliferation mediated by GLP-2 in the animal model rats.     

The Biliary Excretion of 3H–MannitoI and 3H–Ibuterol in Unanaesthetized Rats

Abstract The biliary clearances of ³H–mannitol (5 and 50 μmol/kg) and ³H–ibuterol (diisobutyrate ester of terbutaline) (0.5 and 5 μmol/kg) after intraarterial administration have been studied using unanaesthetized rats with uninterrupted enterohepatic circulation. The mean bile flow was 0.08 ml/min./kg. The biliary clearance of mannitol ranged from 0.06–0.17 ml/min./kg. The biliary clearance of ibuterol and its metabolites (total radioactivity) ranged from 2.05 to 4.81 ml/min./kg and that of the formed terbutaline from 0.53 to 2.05 ml/min./kg indicating a concentrative transfer from the plasma to the bile. The cumulative biliary excretion during the 3 hour sampling period amounted to 1 % of the administered doses of mannitol and 25 % of the doses of ibuterol.     

Decreased biliary excretion of tributylmethyl ammonium in cholestyramine pretreated rats due to reduced formation of ion-pair complexes with hepatic bile salts

The hypothesis that higher molecular weight (MW) quaternary ammoniums (QAs) form lipophilic ion-pair complexes with bile salts in the liver, and are subsequently excreted into bile via a canalicular transporter, P-gp, was re-examined in the present study for its validity. The biliary excretion of tributylmethyl ammonium (TBuMA), a QA with a MW of 200, in bile salt-depleted rats was determined. Depletion was induced by a daily oral administration of a resin, cholestyramine, at a dose of 0.5 g/kg for 2 consecutive weeks, which decreased the concentration of total bile salts in the liver by 38%. When TBuMA was administered intravenously (12 micromol/kg) to these rats, the plasma level, area under the plasma concentration-time curve (AUC), systemic clearance (CL) and volume of distribution (V(ss)) of the compound remained unchanged, whereas bile flow (23.03 vs 16.94 microl/min, p<0.05) and biliary clearance (CL(bile), 12.75 vs 5.34 ml/min/kg, p<0.01) were decreased significantly. These results implied the biliary clearance of TBuMA in rats with bile salt depletion was significantly decreased as a result of decreased ion-pair complexation of TBuMA. The above results are consistent with our hypothesis and the existence of a MW threshold (i.e. 200+/-50 for rats) for the biliary excretion of QAs.     

Clinical investigation of the biliary excretion of cefoperazone in obstructive jaundice

In the present study, we investigated the biliary excretion of cefoperazone (CPZ) in patients with complete obstruction in the lower bile duct governing PTC drainage, i.e., patients with completely blocked enterohepatic circulation. The blockage was observed to cause a delay in the excretion of CPZ due to hepatic dysfunction and the half-life of CPZ levels in serum was as long as 4.9 hours on the average. This is approximately the same as the half-life of 4.8 hours in hepatic dysfunction reported by Belaieff. Biliary concentration of CPZ reached their peak levels within the first 2 to 6 hours. The time to peak in cases with hepatic dysfunction was similar to that reported by observed in patients without hepatic dysfunction Yura et al. In our cases, however, peak biliary concentrations of CPZ were observed to be between 28 to 954 micrograms/ml with a mean of 320.5 micrograms/ml. These peak levels were lower than those reported by several investigators, but sufficiently effective concentrations seem to have been achieved in the bile even in jaundice because MIC80 values of CPZ are reported to be 6 to 10 micrograms/ml against E. coli, Klebsiella, and Enterobacter and 50 micrograms/ml against the most resistant Serratia. As mentioned above, the lowest peak biliary concentration was found to be 28 micrograms/ml and peak levels reached at least 50 micrograms/ml in 8 out of the 10 patients. Urinary concentrations of CPZ reached their peak levels within the first 30 minutes to 2 hours and CPZ urinary recovery ratio in 24 hours was 24.2 to 93.1% with a mean of 64.1%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of phenobarbitone on the distribution and elimination of imipramine in rats

The effect of phenobarbitone on the steady state volume of distribution (Vdss) and the total body blood clearance (CLtot, b) of imipramine and the serum concentration of its metabolite, desipramine was examined. The serum disappearance of imipramine after an 8 mg kg-1 i.v. dose followed a biexponential decline in both control and phenobarbitone-treated rats while the concentration of its metabolite increased in the phenobarbitone-treated rats then rapidly declined compared with that in control rats. Since CLtot,b was nearly equal to the hepatic blood flow (QH), QH may be the rate-determining step of imipramine elimination. In the control rats the Vdss of imipramine was large at 19.9 litre kg-1. In the phenobarbitone-treated rats the pharmacokinetic parameters, biological half-life (t1/2) and Vdss significantly decreased to approximately 23-40% while CLtot,b increased to 126% of those in the control rats, although the latter difference was not statistically significant. The blood-to-plasma concentration ratios (RB) of imipramine and desipramine decreased in the phenobarbitone-treated rats. The urinary excretion ratios of imipramine and desipramine, to the dose of imipramine over 8 h, were less than 1.5% in both groups. These ratios were not significantly changed in the phenobarbitone-treated rats. It was concluded that the significant decrease in t1/2 of the phenobarbitone-treated rats may not be attributed to the changes in CLtot,b and/or in the urinary excretion, but mainly to the decrease in Vdss.