Disposition and excretion of 2,3,7,8-tetrachlorodibenzofuran in the rat

The absorption, distribution, and excretion of the highly toxic halogenated aromatic hydrocarbon, 2,3,7,8-tetrachlorodibenzofuran (TCDF) was studied in the male Fischer rat. [¹⁴C]TCDF was completely absorbed after oral doses of 0.1 and 1.0 μmol/kg body wt. The distribution pattern was the same whether treatment was by oral or intravenous administration. The liver was the major depot of TCDF, with small amounts being redistributed to the skin and adipose tissue. TCDF was primarily excreted via the bile into the feces. Less than 6% was ever removed in the urine. More than half was excreted in the feces within 2 days. [¹⁴C]TCDF-derived radioactivity in the tissues cochromatographed with the parent compound, while in the excreta, only metabolites were detected. Thus, TCDF is readily absorbed, metabolized, and excreted in the feces. This rapid detoxification may account for the relative resistance of the rat to the acute toxicity of TCDF.     

Disposition and excretion of 2,3,4,7,8-pentachlorodibenzofuran in the rat

The disposition of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), a highly toxic environmental contaminant which accumulates in human tissues, was examined in the male Fischer rat after iv and oral exposure. Greater than 70% of an oral dose of 0.1, 0.5, or 1.0 mumol PeCDF/kg body wt was absorbed by the gastrointestinal system. After either oral or iv administration of 0.1 mumol/kg, the dibenzofuran was rapidly removed from the blood and accumulated in the liver and adipose tissue and to a lesser extent in the skin and muscle. Three days after administration, 70% of the iv dose of PeCDF was found in the liver, 7% in the fat, 1% in the skin, and 0.5% in the muscle. Route of exposure had little effect on tissue distribution. TLC analyses indicated that greater than 99% of the [14C]-PeCDF-derived radioactivity which had accumulated in the liver and adipose tissue was unmetabolized PeCDF which was eliminated very slowly (t1/2 = 193 and 69 days, respectively). The whole body half-life calculated from the daily fecal excretion rate was approximately 64 days. Excretion occurred primarily via the feces. No radioactivity was detected in expired air and less than 0.02% was detected in the urine. TLC analysis of fecal extracts indicated greater than 90% of the [14C]PeCDF-derived radioactivity in the feces was polar metabolites of the parent compound. Pretreatment with 500 micrograms PeCDF/kg body wt caused biliary excretion to nearly double. Treatment of bile with beta-glucuronidase or arylsulfatase had little effect on the chromatographic profile. Therefore, PeCDF was readily absorbed from the gastrointestinal tract, concentrated primarily in the liver, and was slowly eliminated from the body as polar metabolites. The long half-life and high body burden of PeCDF suggest that the toxicity of this chemical may be enhanced due to bioaccumulation upon chronic low-level exposure.     

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)     

Disposition and metabolism of radiolabelled pentachloroanisole in rats and rabbits

Male Sprague-Dawley rats and New Zealand White rabbits were administered ¹⁴C-labelled pentachloroanisole (PCA) in corn oil by gavage as single doses of 25 mg/kg and were then placed in individual metabolism cages for as long as 4 days. Peak blood level of radioactivity occurred 6 hr after administration of the dose to rats and between 3 and 4 hr in rabbits; the blood elimination half-life ranged from 8 to 15 hr in rats and averaged 6 hr in rabbits. Rats excreted an average of 54.2% of the administered radiolabel in the urine and 32.4% in the faeces during the 96 hr following the dose; rabbits excreted an average of 84.2 and 13.1% of the radiolabel in the urine and faeces, respectively, during this time. Examination of the metabolites in the rat showed that 60% of the urinary radioactivity was attributable to tetrachlorohydroquinone (TCH). 3% to free pentachlorophenol (PCP) and 29% to conjugated PCP; faecal metabolites were PCP (85.7%), TCH (4.3%) and polar metabolite(s) (10%). In the rabbit, 58% of the urinary radioactivity was attributable to TCH. 8% to free PCP and 34% to conjugated PCP. Faecal metabolites consisted of PCP and conjugated material.     

Disposition of ethmozine in cerebrospinal fluid and plasma of rabbits

The concentration-time profiles of ethmozine, a newly introduced anti-arrhythmic drug, in the cerebrospinal fluid (CSF) and plasma of six rabbits (New Zealand white rabbits of both sexes, 4.0-5.0 Kg) were studied after intravenous bolus administration. CSF samples at various intervals were obtained while the animal was lightly anaesthetized with intravenous thiopentone (40 mg Kg-1) and blood samples at other intervals were taken while the animal was conscious. Blood samples (1 ml) were collected from the implanted cannula of the ear artery while CSF samples (0.3 ml) were obtained from the cisterna magna. The plasma concentrations of ethmozine in six rabbits declined rapidly after intravenous injection for up to 30 min. then slowly over 12 h. Using non-compartmental analysis, the mean (+/- S.E.M.) elimination half-life, mean residence time, plasma clearance and volume of distribution at steady state were 13.9 +/- 9.2 h, 19.9 +/- 13.4 h, 2.3 Lh-1 and 26.8 +/- 7.9 L respectively. The mean CSF-plasma concentration ratios for ethmozine at 0.5, 1.0, 2.0, 4.0, 8.0 and 12.0 h were 0.17, 0.14, 0.16, 0.16, 0.23 and 0.22 respectively. The results suggest that ethmozine is able to penetrate into the CSF from the general circulation and this may be related to its adverse effects on the central nervous system.     

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.     

Disposition of intravenous theophylline-7-acetic acid in rabbits

Theophylline-7-acetic acid (T7AA) was administered intravenously to rabbits so that its distribution and rate of elimination could be ascertained. The analytical techniques used were liquid scintillation counting (¹⁴C) and high pressure liquid chromatography. T7AA was eliminated rapidly in the urine; the T_½ was 11·6 min. This drug appears to accumulate in the kidney because after 60 min, approximately 15 per cent of the intravenous dose was found in that organ.     

Disposition kinetics and metabolism of nicotine-1'-N-oxide in rabbits.

The disposition kinetics and metabolism of nicotine-1'-N-oxide (NNO) are of interest as the reduction of NNO might influence the pharmacokinetics of nicotine in tobacco users. The disposition kinetics of nicotine-1'-N-oxide were characterized in New Zealand rabbits. The clearance of NNO averaged 7.5 ml/min/kg. The half-life averaged 42.6 min and VDss was 0.34 liter/kg. The oral and ip bioavailabilities were 15.1 and 79%, respectively. NNO was reduced to nicotine and cotinine following i.v., oral, and ip injection. The pattern of metabolites after iv dosing suggests that there is systemic reduction of NNO, although the magnitude of that reduction is small, with less than 3% reduced to nicotine. Following oral NNO, 45% was reduced, with a metabolite pattern consistent with presystemic (bacterial or intestinal) metabolism.     

Disposition kinetics of erythromycin in normal and experimentally-induced febrile rabbits.

The disposition kinetics of erythromycin were determined in normal and endotoxin-induced febrile rabbits following intravenous injection of a single dose of 10 mg/kg body weight. In febrile rabbits, body weight, blood pH, total lipids and total proteins in plasma remained unchanged, packed cell volume, albumin and the albumin/globulin ratio reduced while glucose and globulins increased significantly. The mean plasma drug concentration was lower under febrile conditions at all the sampling times except at 480 and 720 min after drug administration where the levels remained the same. The values for t1/2elim and MRT of the drug were observed to be prolonged while that of the Clt reduced and Vd increased in the febrile rabbits. The febrile condition resulted in an alteration in the disposition kinetics of erythromycin suggesting an adjustment of the dosage under febrile conditions.     

Disposition and excretion of intravenous 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) in rats

Polybrominated dibenzodioxins and dibenzofurans are of toxicologic interest due to potential occupational and environmental exposure and because of their structural similarity to the highly toxic chlorinated analogues. The excretion and terminal tissue distribution of [3H]TBDD was studied in male F344 rats for 56 days following single iv doses of .001 or 0.1 mumol/kg. The major tissue depots of radioactivity were liver, adipose tissue, and skin, and tissue distribution was dose-dependent. At 56 days, liver concentrations in the high dose group were disproportionately increased compared to those of the low dose group. Liver:adipose tissue concentration ratios were 0.2 and 2.6 at the low and high doses, respectively. Elimination of radioactivity in the feces, the major route of excretion, and urine was also nonlinear with respect to dose. By Day 56, feces accounted for approximately 50% of the administered dose at the low dose versus 70% at the high dose. Based on fecal excretion, the apparent terminal whole body half-life was estimated to be 18 days for both dose groups. The time-dependent pattern of tissue disposition was characterized at the low dose over a 56-day period. Blood levels of radioactivity declined rapidly with 2% remaining in the blood by 24 hr. Radioactivity levels in the liver peaked by 7 hr and then gradually declined concomitant with a slow accumulation in adipose tissue. The terminal excretion half-life of radioactivity in adipose tissue was estimated to be 60 days. Liver:adipose tissue concentration ratios declined with time. Thus, the overall disposition of TBDD appears similar to that observed for the chlorinated analogue, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The results of these studies are consistent with the hypothesis that TBDD, like TCDD, induces a binding species in the liver which accounts for higher liver:adipose tissue concentration ratios at the high dose. The dose-dependent tissue disposition and excretion kinetics of these compounds suggest important considerations for extrapolations from high to low doses.     

Disposition kinetics of nicotine and cotinine enantiomers in rabbits and beagle dogs

The disposition kinetics of nicotine and cotinine enantiomers was determined in rabbits. The clearance of (R)-nicotine was similar to that of (S)-nicotine, but clearance of (R)-cotinine was twice that of (S)-cotinine. Fractional conversions of both enantiomers of nicotine to cotinine were approximately 50%. These results suggest that in rabbits the biotransformation pathways of cotinine, but not nicotine, are influenced by stereochemistry. The disposition kinetics of nicotine enantiomers in beagle dogs was also studied. In dogs, the clearance of (R)-nicotine was slightly greater than the clearance of (S)-nicotine. Methods for the synthesis of (R)-nicotine and (R)-cotinine of high enantiomeric purity and a gas chromatographic method for determination of nicotine enantiomeric purity are described.     

Disposition of levobunolol after an ophthalmic dose to rabbits

The ocular and systemic disposition of levobunolol (LBUN), an antiglaucoma agent, was studied in albino rabbits. After topical administration to eyes, LBUN was rapidly adsorbed, with 2.5% of the dose bioavailable to the intraocular tissues as intact drug and 46% to the systemic circulation. On passage across the cornea, approximately 4.7% of a topically applied LBUN dose was biotransformed to dihydrolevobunolol (DHB), and subsequently became bioavailable to intraocular tissues. The major sites of ocular metabolism were the cornea epithelium and the iris-ciliary body. Another 12% of the topical LBUN dose entered the systemic circulation as DHB after presystemic biotransformation. Our study indicated a rapid absorption of LBUN into the aqueous humor after topical dosing. The tpeak was 15 min after dosing and the Cmax was 4 micrograms/mL. Dihydrolevobunolol (DHB) was formed steadily and reached a maximum in the aqueous humor 45 min after dosing. After distribution equilibrium had been reached, the aqueous humor concentrations of both LBUN and DHB declined. Six hours after dosing, the concentration of DHB in the aqueous humor was approximately 10 times higher than that of its parent compound. Because DHB is equivalent to its parent compound in beta-blocking activity, its formation in the rabbit eye may contribute to the pharmacodynamic effects observed after topical doses of LBUN.     

Biliary excretion of lead in rats rabbits,and dogs

The disappearance of ²¹⁰Pb from the blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.1, 0.3, 1.0, 3.0, or 10 mg/kg of inorganic lead. The maximal rate of excretion of lead into the bile was approximately 1.0 μg/min/kg after the 3 higher doses. The concentration of lead in the bile was found to be 40–100 times that in the plasma for the 3 lower doses. This was due largely to the higher concentration of lead in the liver than in the plasma (10- to 35-fold higher) and partially to the higher concentration in the bile than in the liver (3- to 4-fold higher). Essentially none of the lead in the bile, plasma, and liver was dialyzable. Lead exhibited a 5-fold greater affinity for liver than bile and a 3-fold greater affinity for liver than plasma. The mitochondrial fraction contained the highest concentration of lead. Changing the rectal temperature of rats altered the biliary excretion of lead markedly; when the temperature was increased from 30 to 40°C, the biliary excretion of lead increased 20-fold. Marked species differences in the biliary excretion of lead were observed. Rabbits excreted lead into the bile at a rate less than one-half, and dogs excreted lead at a rate less than one-fiftieth, that observed in the rat. The results indicate that lead is excreted into the bile of rats against an apparent concentration gradient and that an apparent transport maximum exists. This suggests that the liver may have an active transport mechanism for the excretion of metals.     

黄芪甲苷在兔体内的药动学和在大鼠的排泄(英文)

目的 :研究黄芪甲苷在家兔体内的药动学和在大鼠的排泄。方法 :健康家兔和大鼠一次静脉注射 (静注 )给予黄芪甲苷 4mg·kg- 1,高效液相色谱 蒸发光散射检测器法检测兔血浆和大鼠尿及粪黄芪甲苷浓度 ,用 3P97药动学软件对兔血浆浓度 时间数据进行动力学分析和计算药动学参数 ,并估算大鼠体内的排泄情况。结果 :黄芪甲苷静注给药后 ,T12 α 为 0 .10h ,T12 β 为 1.4h ,Vc 为 0 .15L·kg- 1,VD 为 0 .6L·kg- 1,Cl为 0 .32L·h- 1·kg- 1,AUC为 15mg·L- 1·h。大鼠静注给药后 ,原形从尿和粪排出量分别为给药量的 16 %和 3.2 %。结论 :家兔体内黄芪甲苷的动力学过程符合二室模型 ,大鼠仅有少量原形药物从尿和粪排泄。     

Pharmacokinetic studies on the concomitant administration of piperacillin and cefazolin, and piperacillin and cefoperazone in rabbits

The pharmacokinetics of each drug on the concomitant administration of piperacillin (PIPC) and cefazolin (CEZ) or cefoperazone (CPZ) were studied in rabbits. When rabbits received the consecutive drip infusion administration of CEZ (0.71 mg/kg/minute) and PIPC (1.38 mg/kg/minute) and likewise of CPZ (0.72 mg/kg/minute) and PIPC (1.54 mg/kg/minute) for 1 hour, respectively, the serum half-lives of CEZ and CPZ were respectively prolonged about 1.8 and 1.6 times during drip infusion of PIPC than administered alone. However, when the sequence of administration were reversed, the serum levels of PIPC were not affected by the consecutive drip infusion administration of CEZ and CPZ. To study these findings in detail, the single intravenous dose of 20 mg/kg of CEZ and CPZ were administered under drip infusion of PIPC (2.65-2.93 mg/kg/minute). The serum half-lives of CEZ and CPZ were also prolonged about 5.4 and 1.9 times, respectively, whereas urinary excretion of CEZ, and urinary and biliary excretion of CPZ were reduced by PIPC. Moreover, when the single intravenous dose of 20 mg/kg of PIPC were administered under drip infusion administration of CEZ (0.96-2.60 2.60 mg/kg/minute), the pharmacokinetics of PIPC was not affected by the presence of CEZ. However, under drip infusion administration of CPZ (2.60-2.70 mg/kg/minute), the PIPC serum half-life was prolonged about 1.4 times, and biliary excretion of PIPC was reduced but urinary excretion was not. From the results of renal clearance experiments, tubular secretion appeared to be the predominant mechanism of renal elimination for these three drugs. These results indicate that PIPC influences the pharmacokinetics of both drugs by the competitively inhibiting tubular secretion in CEZ, and tubular secretion and hepatic transport system in CPZ. Therefore, in this respect PIPC seems to have probenecid-like action.     

Mammary excretion of cannabidiol in rabbits after intravenous administration

Abstract— The present study examined the distribution of cannabidiol into milk after an intravenous bolus injection (3 mg kg^?1) to lactating rabbits. Drug concentrations in milk and serum were measured by HPLC. Cannabidiol was excreted into milk rapidly and the drug levels in milk increased over a 4–24-h period following the maternal injection. The mean milk to serum concentration ratio was 25·9, indicating a significant accumulation of the drug in milk.