The high sensitivity of the rabbit to the teratogenic effects of 13-cis-retinoic acid (isotretinoin) is a consequence of prolonged exposure of the embryo to 13-cis-retinoic acid and 13-cis-4-oxo-retinoic acid,and not of isomerization to all-trans-retinoic acid

Previous studies suggested that the rabbit is much more susceptible to the teratogenic action of 13-cis-retinoic acid (13-cis-RA) than the mouse or the rat, while the teratogenicity of all-trans-RA was comparable in these species. In the present study we investigated if pharmacokinetics can explain these species- and structure-related differences. The embryotoxic and teratogenic potential of all-trans-retinoid acid (all-trans-RA) and 13-cis-RA were evaluated in the Swiss hare rabbit after oral administration of daily doses of the two drugs throughout organogenesis, from gestation day (GD) 6 to 18 (plug day=GD 0). All-trans-RA was given at dose levels of 0.7, 2 or 6 mg/kg body weight per day and 13-cis-RA at 3, 7.5 or 10 mg/kg per day. The doses needed to elicit a minimum teratogenic response were found to be 6 mg/kg per day for all-trans-RA and 10 mg/kg per day for 13-cis-RA. Using these doses, transplacental pharmacokinetics of all-trans- and 13-cis-RA were performed. Pregnant rabbits were treated once daily from GD 7 to 12 and plasma and embryo samples were collected for HPLC analysis at various time intervals after the final dose. The main plasma metabolites of all-trans-and 13-cis-RA were all-trans-β-glucuronide (all-trans-RAG) and 13-cis-4-oxo-RA, respectively. The elimination of 13-cis-RA and its metabolites from maternal plasma were much slower than of all-trans-RA resulting in accumulation of the 13-cis-isomers in plasma. Marked differences in the placental transfer of the two drugs and their metabolites were observed. All-trans-RA and all-trans-4-oxo-RA were efficiently transferred to the rabbit embryo, reaching concentrations similar to the plasma levels. On the contrary, the 13-cis-isomers reached the embryo to a lesser extent. Despite its limited placental transfer, a considerable embryonic exposure to 13-cis-RA and 13-cis-4-oxo-RA was noticed after treatment with isotretinoin, as indicated by their area-under-the-concentration-time-curve (AUC) values in the embryo, which were in the same range as the corresponding AUC value of all-trans-RA after treatment with the all-trans-isomer. Our results suggest that the high sensitivity of the rabbit to the teratogenic effects of 13-cis-RA can be attributed mainly to the 13-cis-isomers and not to isomerization to all-trans-RA. The significant exposure of the rabbit embryo to 13-cis-RA and its 4-oxo metabolite is a result of their very slow excretion rates from the maternal organism. Furthermore, this study supports the view that embryonic AUC values should be considered as the most suitable pharmacokinetic correlate to retinoid induced teratogenesis. Results of the pharmacokinetic study have been presented in part at the 20th Conference of the European Teratology Society, August 31–September 3, 1992, Würzburg, Germany, and have appeared in a short abstract (Tzimas et al. 1992) Supported by a grant from the Deutscher Akademischer Austauschdienst     

Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats.

Cosalane and dihydrocosalane are potent inhibitors of HIV replication with a broad range of activity. The purpose of this study was to investigate: 1) the pharmacokinetic disposition of both cosalane and dihydrocosalane in male Sprague-Dawley rats, and 2) biliary excretion, enterohepatic circulation, and tissue distribution of cosalane after i.v. and/or oral administration. Animals were administered i.v. (10 mg/kg) cosalane or dihydrocosalane through a jugular vein to obtain plasma profiles. Dose dependence of cosalane was studied over a dose range of 1.0 to 10 mg/kg. The extent of enterohepatic recycling, biliary excretion, and tissue distribution were studied after i.v. administration. Both cosalane and dihydrocosalane exhibited a biexponential disposition with very long half-lives of 749 +/- 216 and 1016 +/- 407 min, along with very large volumes of distribution 23.1 +/- 4.4 and 24.4 +/- 2. 5 liter/kg, respectively. Both cosalane (nondetectable) and dihydrocosalane (<1%) showed very poor oral bioavailability. The biliary and renal excretions of cosalane were found to be negligible with no detectable metabolites either in urine or bile. After oral administration, more than 87% of the cosalane dose was excreted in the feces as the parent compound. Also, cosalane was sequestered significantly in liver with quantifiable levels in all tissues tested, even 48 h after the dose was administered. Therefore it was concluded that the poor oral bioavailability of cosalane may be due to its poor enterocytic transport coupled with sequestration in liver parenchymal cell membrane layers.     

The Biliary Elimination and Enterohepatic Circulation of Ibuprofen in Rats

The biliary and urinary excretion of ibuprofen and its metabolites were determined in rats after intravenous and peroral administration of 25 and 100 mg/kg of the drug. Within 24 hours 48% of the low i.v. dose and 59% of the high i.v. dose were eliminated via bile as ibuprofen and its metabolites. Following oral administration 40 to 41% of the dose were recovered in bile, whereas 16 to 32% of the dose were eliminated in urine, resulting in an overall drug recovery of 66 to 79% within 24 hours. Upon infusion of bile containing ibuprofen and its metabolites into the duodenum substantial enterohepatic cycling of the drug occurred in the rat.     

Excretion and metabolism of intramuscularly administered [14C]-haloperidol decanoate in rats

Urinary, fecal and biliary excretion, together with enterohepatic circulation, of radioactivity were studied after intravenous (50 mg eq/kg) and intramuscular (5 and 50 mg eq/kg) administration of [14C]-haloperidol decanoate in rats. The composition of urinary and biliary metabolites was also examined. The rate of excretion after intravenous administration lowered rapidly with the half-life of about 1.5 days and about 95% of dose was excreted in excreta within 10 days. Shortly after intramuscular administration, the rate of excretion lowered rapidly but then more gradually later (half-lives after administration of 5 and 50 mg eq/kg were 16.4 and 11.2 days, respectively). About 90% of dose was excreted within 42 days after intramuscular administration. About 1.6% of dose/day was excreted in the bile during 15-17 days after intramuscular administration, of which about 30% was reabsorbed within 24 h (enterohepatic circulation). The major urinary metabolite was p-fluorophenylaceturic acid and the biliary metabolite, glucuronide and sulfate of haloperidol. No unchanged decanoate was detected in the excreta.     

Absorption and excretion of suprofen in rats

DL-2-(4-(2-Thienylcarbonyl)phenyl)propionic acid (suprofen, S) was rapidly absorbed in rats after oral administration. Blood levels after a single oral dose of 2, 10, 50, or 100 mg/kg of 3H-S reached maxima within 30 min and were dose-dependent. The major portion of the drug was shown to be absorbed from the upper part of the small intestine and a portion from the stomach. The radioactivity in rat plasma was extensively bound to the plasma protein in vivo; this was found to be unchanged S and four metabolites. Elimination of S and its metabolites from blood was rapid; 3H was mostly excreted in the urine and feces within 24 hr after oral administration of 3H-S. No significant amounts of 14CO2 were excreted in expired air after administration of 14C-S. Rat urine contained S and four metabolites found in rat plasma, accounting for about 60% of the urinary radioactivity. After rats with biliary fistulas were given an oral dose of 2 mg/kg of 3H-S, 41% of the dose was excreted in the bile during 48 hr; there was significant enterohepatic circulation. When single or 21 consecutive daily doses of 3H-S were administered to rats, the blood levels after the multiple doses were higher than those after a single dose but no significant difference was found in excretion of 3H.     

Influence of curcumin on cyclosporin-induced reduction of biliary bilirubin and cholesterol excretion and on biliary excretion of cyclosporin and its metabolites

We investigated the ability of curcumin, which can be extracted from different Curcuma species, to prevent cyclosporin-induced reduction of biliary bilirubin and cholesterol excretion, and its influence on biliary excretion of cyclosporin (CS) and its metabolites in the bile fistula model in rats. I.v. injection of curcumin (25 and 50 mg/kg) after 30 min increased dose-dependently basal bile flow (30 microliters/kg/min) up to 200%, biliary bilirubin excretion (3000 pmol/kg/min) up to 150%, and biliary cholesterol excretion (22 nmol/kg/min) up to 113%. CS (30 mg/kg) reduced bile flow to 66% and biliary excretion of bilirubin and of cholesterol to 33% of the basal value 30 min after i.v. injection. I.v. administration of curcumin (25 and 50 mg/kg) 30 min after CS increased bile flow dose dependently again to 130% for 1 hour and biliary excretion of cholesterol and of bilirubin to 100% of the basal value for 30 and 150 min, respectively. Injection of curcumin 15 min before CS prevented the CS-induced drop of bile flow at 50 mg/kg and reduction of biliary bilirubin excretion already at 25 mg/kg until the end of the experiment (180 min). The CS-induced reduction of biliary cholesterol excretion, however, was not prevented by curcumin. Finally, the biliary excretions of CS (1200 ng/kg/min) and its metabolites (1200 ng/kg/min) were slightly reduced by curcumin at a dose of 50 mg/kg (to 83% of the initial values). The clinical importance of these controversial effects remains to be shown.     

The disposition and pharmacokinetics of ketoconazole in the rat

The disposition, biliary excretion, and pharmacokinetics of ketoconazole in Sprague-Dawley rats were determined after intravenous administration. Greater than 80% of the radioactivity after a 5 mg/kg iv dose of 3H-ketoconazole was excreted in the feces. Urinary excretion was essentially complete after 48 hr; however, fecal excretion was prolonged over a 7-day period. Biliary excretion of radioactivity averaged 54.3 +/- 18.0% of the dose over a 7.5-8-hr period in pentobarbital-anesthesized rats. The possibility of enterohepatic recirculation was examined using a linked rat technique. Less than 2% of the radioactivity was found in the recipient bile over 9-12 hr. In eight male rats, the plasma pharmacokinetics of ketoconazole, as determined by an HPLC assay with fluorescence detection, were as follows: VD = 655 +/- 91 ml/kg, Cl = 14.4 +/- 5.1 ml/min/kg, and t 1/2 = 35.0 +/- 12.3 min. Three of the rats were given an additional oral dose to determine absolute bioavailability. The time to peak was 30-60 min, and the bioavailability was 35.8 +/- 3.55%. Previous studies have indicated that ketoconazole is well absorbed in rats; therefore, the poor bioavailability is probably due to first pass metabolism. The prolonged fecal excretion of radioactivity from an intravenous dose was probably caused by slow elimination of ketoconazole metabolites.     

The pharmacokinetics of hexachlorobenzene in male beagles. Distribution, excretion, and pharmacokinetic model

The distribution of hexachlorobenzene (HCB) was studied in male beagles after a single 1-mg/kg iv dose of either 14C-HCB or unlabeled HCB. Distribution was also determined in animals after seven daily oral administrations of either 10 mg/kg or 100 mg/kg HCB. Excretion of HCB and metabolites through urinary and fecal routes was studied in all four animals receiving 14C-HCB. In addition, total bile was collected from one of the animals receiving 14C-HCB to determine the importance of biliary excretion. Immediately after iv administration, a large proportion of the dose was distributed to the lungs. From the lungs, HCB was rapidly distributed to highly perfused tissues including the visceral organs and brain. Further redistribution of HCB from highly perfused tissues to adipose tissue occurred at a much slower rate. In animals receiving daily oral doses of 10 or 100 mg of HCB per kg, adipose tissue was again found to accumulate the highest concentrations of HCB. Excretion of HCB and metabolites occurred primarily through fecal elimination, with urinary excretion being of less importance. Fecal excretion was found to be composed of two separate processes, biliary excretion and intestinal excretion. Of these two processes, biliary excretion was shown to be the major contributor to fecal excretion. After single 1-mg/kg IV doses of 14C-HCB in three beagles, blood, urine, and feces were monitored over a 12-week period for 14C content. Computer-assisted pharmacokinetic models were constructed to characterize these data. A three-compartment mammillary model provided the optimum fit to the observed data. Biological half-life values were projected to range from 6 weeks to 3 years.     

Biliary excretion of arsenic in rats,rabbits, and dogs

The disappearance of ⁷⁴As from blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.01, 0.46, 1.0, 2.1, and 4.6 mg/kg of arsenic given as the trichloride. Arsenic disappearance from plasma was biphasic; the half-life during the late phase was greater than 2 hr. Even though the arsenic was injected iv, the concentration in the blood increased through the first 2 hr. Arsenic was rapidly excreted into the bile, reaching its highest rate of excretion 6 min after administration, after which it rapidly decreased. This rapid decrease in excretion is due to redistribution of arsenic from the liver to the blood. Arsenic enters bile against an apparent bile/plasma concentration gradient of 630, 8 min after 1 mg/kg of arsenic. At this time the liver/plasma gradient is 17 and the liver/bile gradient is 37. Twenty-five percent of the arsenic administered to bile duct-cannulated rats is excreted into the bile within 2 hr. However, less than 10% of the administered dose is excreted into the feces of intact rats over a 7-day period. In the rabbit and dog, arsenic is excreted into the bile at a much slower rate. These data demonstrate that arsenic is excreted into the bile, and this occurs against a large bile/plasma concentration gradient in rats, suggesting excretion by an active transport mechanism. However, the overall importance of bile as a route of elimination for arsenic is minimized due to enterohepatic circulation and species variations in its biliary excretion rate.     

Stimulation of nonbiliary, intestinal excretion of hexachlorobenzene in rhesus monkeys by mineral oil

Four rhesus monkeys were administered various doses of hexachlorobenzene (HCB) po, to achieve widely varying adipose tissue levels. One month later, each animal was provided with a bile duct bypass allowing for interruption of the enterohepatic circulation (EHC). Effects of mineral oil-supplemented diet and/or interruption of the EHC on urinary, biliary, and fecal excretion of HCB and its metabolites were quantified. Urinary excretion of HCB was not affected by mineral oil but was reduced 20 to 60% by interruption of the EHC. Similarly, biliary excretion of HCB was also reduced 25 to 60% by interruption of the EHC and was not altered by mineral oil. Fecal excretion was increased about fivefold by mineral oil, whereas interruption of the EHC had no effect on the amount of HCB in feces. Results demonstrate that interruption of the EHC reduced urinary and biliary excretion of HCB metabolites, whereas mineral oil specifically stimulated intestinal excretion of the parent compound.     

Pharmacokinetics of epinastine and a possible mechanism for double peaks in oral plasma concentration profiles.

The pharmacokinetics of epinastine (EPN), an anti-allergic agent, was investigated in rats. The plasma concentration-time profile of EPN after intravenous (i.v.) administration was triexponential. After oral administration of EPN (7.5 and 20 mg/kg), the drug was rapidly absorbed, and Cmax was reached 2 h after dosing. A minor secondary peak was observed in EPN plasma concentration-time profiles at both doses. The bioavailability of EPN after oral dosing was 41 and 40%. The kinetic parameters (T 1/2, AUC and MRT) for unlabeled EPN were much smaller than those for 14C-EPN, which has already been reported. The total biliary excretion of EPN at a 7.5 mg/kg dose was 15.5% of the dose, but the percentage of conjugates in bile was extremely low and about 11% of the total biliary excretion. The increase in the plasma concentration in bile duct-linked rats after oral administration of EPN (20 mg/kg) was not observed, indicating that a secondary increase in drug concentration based on enterohepatic circulation was ruled out. When the gastrointestinal (GI)-transit of phenol red (PR) after oral administration of EPN (20 mg/kg) was estimated, the GI-transit of PR was significantly delayed, and at 3-4 h after dosing half of the PR dose reached the jejunum. The remaining EPN in the small intestine after oral administration (7.5 mg/kg) reached peak levels 2 h after dosing, but then partly increased again at 4 h. As a result, it was clarified that the double peaks observed after oral doses are mainly due to the delayed absorption of a part of EPN, based on the reduction in gastric motility caused by the drug.     

Comparative subacute toxicity of all-trans- and 13-cis-retinoic acid in Swiss mice

Swiss mice were treated once a day for 21 days with all-trans- or 13-cis-retinoic acid administered ip or po. The LD50 of all-trans-retinoic acid was 31 mg/kg ip and 1100 mg/kg po; the LD50 of 13-cis-retinoic acid was 140 mg/kg ip and 26,000 mg/kg po. However, after 21 consecutive days of treatment, fractured bones were observed in treated animals at all tested doses of 13-cis-retinoic acid and at doses of all-trans-retinoic acid higher than 3 mg/kg ip or 10 mg/kg po. By either route of administration, 13-cis-retinoic acid produced the same number and incidence of fractures at doses three to five times that of all-trans-retinoic acid administered by the same route. Treatment with 13-cis-retinoic acid ip resulted in a dose-related decrease in the red blood cell count, but ip administration of all-trans-retinoic acid did not. The concentration of albumin, the serum transport protein for these compounds, was changed only after low oral doses of all-trans-retinoic acid. The appearance of fractured bones was not always associated with elevated plasma alkaline phosphatase concentrations. Based on these parameters of toxicity, 13-cis-retinoic acid was less toxic than all-trans-retinoic acid.     

Effect of diphenylhydantoin on the biotransformation and biliary excretion of imipramine in rats.

1. Rats with biliary fistula excrete 18% of an intraperitoneal dose of [14C]imipramine (80 mg/kg) in bile within 2-5 h. Diphenylhydantoin (46 mg/kg) simultaneously administered intravenously decreases the biliary excretion of imipramine plus metabolites to 7% dose. With or without diphenylhydantoin, the highest biliary concentration of imipramine plus metabolites occurs 30-60 min after dosage. 2. With or without administration of diphenylhydantoin, 83% of the bile radioactivity is present as the conjugated 2-hydroxylated metabolites of imipramine. With imipramine alone, more conjugated 2-hydroxydesmethyl-imipramine than conjugated 2-hydroxyimipramine is excreted in the bile. Diphenylhydantoin reverses this order. 3. Administration of diphenylhydantoin does not significantly alter the concentration of imipramine plus metabolites in plasma, liver, lung and brain measured at five consecutive 30 min periods after dosage.     

Pharmacokinetic modulation of irinotecan metabolites by sulphobromophthalein in rats

The purpose of this study was to modulate the pharmacokinetics of irinotecan metabolites, SN-38 and SN-38-glucuronide, by possibly reducing biliary excretion, which in turn could lower irinotecan toxicity. SN-38-glucuronide is associated with severe diarrhoea that occurs after irinotecan therapy as a result of enteric injury caused by SN-38. Sulphobromophthalein is used clinically as a drug for testing liver function and is considered to be a safe drug. We investigated the effect of sulphobromophthalein on the disposition of irinotecan metabolites after CPT-11 (7-ethyl-10-[10-4-(1-piperidino)-1-piperidino]-carbonyloxy-camptothecin) administration. Wistar rats were administered CPT11 (500 microg/body) in saline as a bolus injection into the femoral vein through a catheter. The volume of drug solution injected into each animal was 1 mL. Rats were either administered CPT-11 alone or simultaneously with sulphobromophthalein (20 mg/body). After administration, blood and bile samples were taken at appropriate intervals and analysed by HPLC. Co-administration of sulphobromophthalein partially inhibited the biliary excretion of SN-38-glucuronide with a concomitant increase in its area under the plasma concentration-time curve (AUC) but did not significantly alter the biliary excretion and AUC of the active metabolite SN-38. These results suggested that cotreatment of CPT-11 with sulphobromophthalein might decrease intraluminal SN-38 concentrations without altering the pharmacokinetics of SN-38.     

Excretion and biotransformation of cisapride in rats after oral administration

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after single (10, 40, and 160 mg/kg) and repeated (10 mg/kg/day) po administration to rats, using three different radiolabels. In fasted rats, cisapride was absorbed almost completely, except for the 160 mg/kg dose. Cisapride was metabolized extensively to at least 30 metabolites. The excretion of the metabolites amounted to more than 80% of the dose at 24 hr and was almost complete at 96 hr after dosing. In bile duct-cannulated rats, 60% was excreted in the bile within 24 hr, 45% of which underwent enterohepatic circulation. The main urinary metabolites, 4-fluorophenyl sulfate and norcisapride, primarily resulted from the N-dealkylation at the piperidine. Another major metabolic pathway was aromatic hydroxylation, occurring on either the 4-fluorophenoxy or the benzamide rings. The resulting phenolic metabolites were eliminated as conjugates in the bile; a large portion of them were subjected to a rapid enterohepatic circulation before their final excretion in the feces. Minor metabolic pathways included piperidine oxidation, O-dealkylation, O-demethylation of the methoxy substituent at the benzamide, and amine glucuronidation. Only minor quantitative dose- and sex-dependent differences could be observed for the mass balance of the metabolites. Upon repeated po dosing, steady state excretion rates were already attained after two to three doses, and excretion and metabolite patterns were very similar to those after single dose administration.     

Host-mediated bacterial mutagenesis and enterohepatic circulation of benzidine-derived mutagenic metabolites in rodents

1. Administration of benzidine (100 mg/kg, i.p.) to bile duct-cannulated rats led to a sustained excretion of metabolites in bile which, following glucuronide hydrolysis, were mutagenic to Salmonella typhimurium strain TA98. 2. When the biliary metabolites were re-infused into the duodena of a further group of rats, enterohepatic circulation of mutagens was indicated by extensive re-excretion of biliary mutagens in the recipients. 3. Furthermore, in mouse host-mediated mutagenicity assays, both i.p. injection of benzidine (100 mg/kg) and intracaecal administration of rat biliary metabolites of benzidine produced a mutagenic response in Salmonella typhimurium strain TA98 cells isolated from the liver. 4. The results indicate that enterohepatic circulation adds to the biological persistence of reactive metabolites of benzidine and may contribute to the carcinogenicity of this aromatic amine.     

Pharmacokinetics of morphine and its surrogates. VIII: Naloxone and naloxone conjugate pharmacokinetics in dogs as a function of dose and as affected by simultaneously administered morphine

Reversed-phase HPLC assays with electrochemical detection, developed to quantify naloxone, 6 beta-naloxol, and their hydrolyzed conjugates in biological fluids provided assay sensitivities of 10 to 20 ng/mL in plasma, urine, and bile. These fluids were monitored in dogs after iv bolus administrations of 0.47 and 4.7 mg/kg of naloxone. Plasma concentration-time data were well fitted by the sums of two exponentials with two sequential half-lives of 11 +/- 1 (SEM) and 56 +/- 3 min. Pharmacokinetics were dose-independent; total and renal clearances were 1334 +/- 133 mL/min and 42 +/- 9 mL/min, respectively, with a renal clearance of 65 +/- 5 mL/min for the conjugate. The percentage of the dose excreted in the urine as naloxone was 4.4 +/- 1.0%. There was a possible dose-dependent excretion of conjugate with 46 +/- 1 and 22 +/- 5% of the dose renally excreted at the high and low doses, respectively. In incomplete biliary cannulation, 13 and 18% were collected as conjugate in the bile of two bile-cannulated dogs. There was negligible biliary secretion of unchanged naloxone. Neither 6 beta-naloxol nor its conjugates were metabolites of naloxone in dogs. The simultaneous administration of naloxone does not reverse the dose-dependent pharmacokinetic perturbations of morphine. Morphine significantly lessened its own body, renal, and biliary clearances, as well as those of naloxone, and also lowered their apparent overall volumes of distribution. Plasma levels of naloxone and its conjugate were elevated with simultaneous morphine administration. Urinary flow rates were also greatly lessened and initial renal shut-down was implied at the higher morphine dose. Thus, the established competitive antagonistic action of naloxone on morphine does not extend to the reversal of the biological feedback effects of morphine on the metabolism and excretion of itself and simultaneously administered naloxone.     

Effects of protein-calorie malnutrition on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats

The pharmacokinetic parameters of DA-7867, a new oxazolidinone, were compared after intravenous and oral administration at a dose of 10 mg x kg(-1) to control rats and rats with protein-calorie malnutrition (rats with PCM). After intravenous administration of 10 mg x kg(-1) DA-7867 to rats, metabolism of the drug was not considerable and after 14 days approximately 85.0% of the dose was recovered as unchanged drug from urine and faeces. After intravenous administration to rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) was significantly smaller (10800 vs 6990 microg min x mL(-1)) compared with control rats. This may have been due to significantly faster total body clearance (CL, 0.930 vs 1.44 mL x min(-1) x kg(-1)). The faster CL in PCM rats could have been due to significantly faster non-renal clearance (0.842 vs 1.39 mL x min(-1) x kg(-1) due to significantly greater gastrointestinal (including biliary) excretion; the amount of unchanged DA-7867 recovered from the entire gastrointestinal tract at 24 h was significantly greater (1.19 vs 4.28% of intravenous dose)) because the renal clearance was significantly slower in PCM rats (0.0874 vs 0.0553 mL x min(-1) x kg(-1)). After oral administration to PCM rats, the AUC was significantly smaller compared with control rats (7900 vs 4310 microg x min x mL(-1)). This could have been due to a decrease in absorption from the gastrointestinal tract.     

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.     

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.