The metabolism of the surfactants dodecyl sulfonate and hexadecyl sulfonate in the rat.

When [1-¹⁴C]dodecyl sulfonate and [1-¹⁴C]hexadecyl sulfonate were administered orally and ip to free-ranging rats and iv to anesthetized rats, the major route of excretion of radioactivity was urinary. Small amounts only of parent surfactant appeared in the feces of animals dosed orally with [1-¹⁴C]dodecyl sulfonate, but large amounts of [1-¹⁴C]hexadecyl sulfonate were found in the feces of animals dosed similarly with this surfactant. Thus, fecal radioactivity represents incomplete absorption of material from the gastrointestinal tract, the permeability of which may depend upon the water solubility of the administered surfactant. The pattern of excretion with either compound was essentially unchanged when animals were pretreated with an antibiotic, and thus the gut flora play no significant part in the metabolism or absorption of these surfactants. No biliary elimination with either surfactant was detected following the iv administration, confirming that the fecal radioactivity represented unabsorbed material. The intraperitoneal administration of dodecyl [³⁵S]sulfonate to rats and analysis of the urinary products showed that no desulfonation takes place. Analysis of the urine of rats following the administration of either [1-¹⁴C]dodecyl sulfonate or [1-¹⁴C]hexadecyl sulfonate revealed the same single metabolite from both surfactants. This metabolite was purifed and identified as butyric acid 4-sulfonate by radioactive glc, mass spectrometry, and cochromatography of its dimethyl derivative. The identity of the urinary metabolite indicates that both dodecyl sulfonate and hexadecyl sulfonate are degraded in the rat by ω,β-oxidation. Whole body autoradiography demonstrates that the liver is the major site of metabolism regardless of the route of administration.     

Pharmacokinetics and bioavailability of diclofenac in the rat.

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac bioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.     

The Acute Toxicity of BIOLF-143 in the Rat

The Acute Toxicity of BIOLF-143 in the Rat. ECOBICHON, D. J.,MEKHAEL, K. M., MAJOR, P., AND OGILVIE, K. K. (1988). Fundam.Appl. Toxicol. 10, 313-320. BIOLF-143, an experimental, purine-basedacyclic nucleoside, was administered by iv or ip injection toyoung, adult, male and female Sprague-Dawley rats in order todetermine the (1) pharmacokinetic disposition, (2) route andrate of excretion, and (3) acute toxicity. HPLC analysis ofplasma, hepatic, and renal tissue levels was conducted followingiv injections of 50 and 100 mg/kg and ip injections of 500 mg/kg.Metabolism/excretion studies were conducted following ip injectionsof BIOLF-143 (100 mg/kg). The assessment of acute toxicity wasdone following the ip injection of agent (250 mg/kg/hr for 8consecutive hr). BIOLF-143 was rapidly distributed in the body,the estimated half-life in blood plasma being 18–23 min.The molecule was essentially unbound to plasma proteins (99%free) and was excreted unchanged in the urine. The recoveryof the parent compound was 74.3 ± 5.9/ and 88.5 ±15.9% for male and female rats, respectively, with no metabolitesor unidentifiable peaks being detected in HPLC chromatograms.No overt toxicity or untoward signs of latent toxicity wereobserved in the animals receiving doses up to 2000 mg/kg ip.No residues were detected in tissues at 24 hr post-treatment.A potential target organ in subchronic studies might be thekidney. High residue levels of BIOLF-143 were detected 1.0 hrpost-treatment; however, the organ had cleared all residuesby 24 hr after administration.     

Disposition of a low dose of 14C-bisphenol A in male rats and its main biliary excretion as BPA glucuronide.

Bisphenol A (BPA) is a weak xenoestrogen mass-produced with potential human exposure. The disposition of bisphenol A in male Fischer-344 (F344) rats dosed orally (100 or 0.10 mg/kg) or intravenously (0.10 mg/kg) was determined. Smaller amounts of the dose appeared in the urine. The main excretion route was feces in rats irrespective of dose and administration route. The biliary excretion during 6 h was 58-66% after iv dosing and 45-50% after oral dosing at 0.10 mg 14C-BPA/kg. Toxicokinetic parameters obtained from 14C-BPA-derived radioactivity in blood were the terminal elimination half-life, t1/2beta = 39.5 h, and total body clearance, CLtot = 0.52 l/h/kg after iv dosing of 0.10 mg 14C-BPA/kg to male rats. The blood concentration reached its maximum of 5.5 ng-eq/ml at 0.38 h after oral dose. AUC(0-6 h), AUC(0-48 h), and AUCinf of 14C-BPA-derived radioactivity, were 34, 118, and 192 ng-eqh/ml for the iv dose and 18, 102, and 185 ng-eqh/ml for the oral dose, respectively. The oral bioavailability of F(0-6 h), F(0-48 h), and Finf were 0.54, 0.86, and 0.97, respectively. The 14C-BPA-derived radioactivity was strongly bound to plasma protein (free fraction, fu = 0.046) and preferentially distributed to the plasma with a blood/plasma ratio of 0.67. From the bile of male rats orally dosed at 100 mg/kg, we have isolated and characterized BPA glucuronide (BPA-gluc) by ESI/MS, 1H and 13C NMR spectroscopy. HPLC analysis showed that BPA-gluc was the predominant metabolite in bile and urine. Unchanged BPA was mostly detected in feces. These results suggest that BPA is mainly metabolized to BPA-gluc and excreted into feces through the bile and subject to enterohepatic circulation in rats irrespective of dose and administration route.     

Distribution, excretion and skeletal muscle effects of the mycotoxin [C]cyclopiazonic acid in rats

The distribution of the mycotoxin, cyclopiazonic acid (CPA), in tissues and its excretion in urine and faeces was studied in male Sprague-Dawley rats. Radiolabelled CPA was biosynthetically produced by cultures of Penicillium griseofulvum and was administered to rats either intraperitoneally (ip) or intragastrically (ig). Radiolabelled material was excreted in both urine and faeces from rats dosed by either route. There was no excretion of radioactivity as expired ¹⁴CO₂. Biliary excretion apparently had a major role in the disposition of CPA, since 38% of the dose of radioactivity was excreted in the faeces of ip-dosed rats within 72 hr. Skeletal muscle tissue contained 48% of the radioactive dose 6 hr after either ip or ig administration. At 72 hr, skeletal muscle of the ip-dosed rats contained 3% of the dose, whereas rats dosed ig retained 8% of the dose in muscle. Degeneration was observed in muscle from rats treated with 8 mg CPA/kg/day for 4 days. The results indicate that some of the toxic effects observed in animals exposed to CPA (hyperaesthesia, hypokinesis, abnormal posture, opisthotonos and convulsions) may be due in part to direct effects of the toxin on muscle. Furthermore, if CPA or its metabolic products distributes in the tissues of other animals as it does in the rat, the potential exists for the exposure of humans to this mycotoxin by consumption of the meat of domestic animals fed contaminated feed.     

The Relative Bioavailability and Metabolism of Bisphenol A in Rats Is Dependent upon the Route of Administration

Bisphenol A (BPA) is used to produce polymers for food contactapplications, thus there is potential for oral exposure of humansto trace amounts via the diet. BPA was weakly estrogenic inscreening assays measuring uterine weight/response, althoughmuch higher oral doses of BPA were required to elicit a uterotropicresponse as compared to other routes of administration. Theobjective of this study was to determine if a route dependencyexists in the pharmacokinetics and metabolism of ¹⁴C-labeledBPA following single oral (po), intraperitoneal (ip), or subcutaneous(sc) doses of either 10 or 100 mg/kg to Fischer 344 rats. Resultsindicated a marked route dependency in the pharmacokineticsof BPA. The relative bioavailability of BPA and plasma radioactivitywas markedly lower following oral administration as comparedto sc or ip administration. The major fraction of plasma radioactivityfollowing oral dosing was the monoglucuronide conjugate of BPA(68–100% of plasma radioactivity). BPA was the major componentin plasma at Cmax following sc or ip administration exceededonly by BPA-monoglucuronide in females dosed ip. Up to fouradditional unidentified metabolites were present only in theplasma of animals dosed ip or sc. One of these, found only followingip administration, was tentatively identified as the monosulfateconjugate of BPA. The monoglucuronide conjugate was the majorurinary metabolite; unchanged BPA was the principal componentexcreted in feces. These results demonstrated a route dependencyof BPA bioavailability in rats, with oral administration resultingin the lowest bioavailability, and offer an explanation forthe apparent route differences in estrogenic potency observedfor BPA.     

Absorption, distribution and excretion of 3-(sulfamoyl[14C]methyl)-1,2-benziosoxazole (AD-810) in Rats, Dogs and Monkeys and of AD-810 in Men

Disposition of 3 - (sulfamoyl[14C]methyl) - 1,2-benzisoxazole ( [14C]AD-810) in rats, dogs and monkeys after oral administration in 20 mg/kg was studied. In preliminary human studies, healthy subjects ingested 200 mg of AD-810. [14C]AD-810 was found to be completely absorbed from digestive tracts in animals, since urinary and biliary excretion accounted for virtually total recovery of dosed radioactivity. Plasma levels reached maxima at several hours after administration in all species examined and decreased exponentially. In rats, tissue levels were virtually similar to plasma levels indicating rather even distribution in the body, and tissue radioactivity disappeared with the similar rate to plasma. Autoradiographic findings on the distribution were consistent with radiometric results. Radioactivity was evenly distributed in fetus in the pregnant rat with the similar level to maternal tissue levels. Like other sulfonamide derivatives, AD-810 was markedly taken up by erythrocytes in all species. [14C]AD-810 radioactivity was mostly excreted within 48 to 72 h after administration and its major route was urine in animals. In men, excretion of unchanged AD-810 and its metabolite in urine was found to be rather slow. No significant differences were found in absorption, distribution and excretion of radioactivity after 7 consecutive daily oral dosings of [14C]AD-810 in rats.     

The effect of altered hepatic function on the toxicity, plasma disappearance and biliary excretion of diethylstilbestrol

The present investigation was prompted by the observation that the toxicity of diethylstilbestrol (DES) was about 140 times greater in bile duct-ligated (BDL) rats than in control rats when dimethylsulfoxide was the vehicle (24-hr LD50: 0.75 vs 100 mg/kg, respectively). The DES was also more toxic (about 70 times) in the BDL rats when ethyl alcohol was the solvent (0.47 vs 34 mg/kg), and was 5 times more toxic in the BDL rats when administered in propylene glycol (100 vs 530 mg/kg). Since it appeared that altered hepatic function markedly alters the acute toxicity of DES, the plasma disappearance and biliary excretion of DES (0.118 mg/kg, iv) were measured in control rats and in rats with altered hepatic function (produced by surgical removal of two-thirds of the liver, ip injection of 1 ml CCl₄/kg, or bile duct ligation). All three procedures of altering hepatic function decreased the plasma disappearance of DES. In the BDL rats, the total plasma concentration of DES did not decrease over the 2-hr period, suggesting that even when the biliary route of excretion is blocked, other routes are not efficent for the excretion of DES. During the furst 15 min after DES administration, the biliary excretory rate of DES was 2.1 μg/min/kg in control rats and 1.2 μg/min/kg in the rats that had a $\text{2}\text{3}$ hepatectomy or CCl₄. Therefore, impaired hepatic function increased the plasma concentration and toxicity of DES as it decreased its conjugation and biliary excretion.     

Pharmacokinetics and bioavailability of diclofenac in the rat

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac hioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.The present work is part of a research project developed with a grant for the Plan Nacional de I + D (FAR 90-0092) of the Ministry of Industry and Energy of Spain.     

Subcutaneous administration of sterically stabilized (stealth) liposomes is an effective sustained release system for 1-β-d-arabinofuranosylcytosine

We have previously demonstrated that 1-β-D-arabinofuranosylcytosine (ara-C) entrapped in long-circulating formulations of liposomes (Stealth, or sterically stabilized) was an effective sustained release system following intravenous (iv) or intraperitoneal (ip) administration (Cancer Res. 52, 2431-2439). We have recently shown that, following subcutaneous (sc) administration, Stealth liposomes can achieve substantial levels in the circulation. The therapeutic effect of sc-administered liposomal ara-C against murine L1210 leukemia was examined as a function of route of injection, liposome size, and liposome composition. When the liposomes contained polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) and cholesterol, sc injection was as effective in increasing lifespan as iv injection against iv or ip tumor. This effect was independent of liposome size or fluidity of the phospholipid. Liposomes lacking PEG-DSPE or lacking cholesterol were significantly less efficacious. Long-term survivors could be obtained following three weekly sc injections of PEG-liposomes.     

Role of rat multidrug resistance protein 2 in plasma and biliary disposition of dibromosulfophthalein after microsomal enzyme induction

We have previously demonstrated that microsomal enzyme inducers phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN), but not 3-methylcholanthrene (3-MC) and benzo(a)pyrene (BaP), increase expression and function of rat Multidrug Resistance Protein 2 (Mrp2), a canalicular organic anion transporter. Thus, the purpose of this study was to determine whether Mrp2 protein induction alters the biliary and plasma dispositions of dibromosulfophthalein (DBSP). After four daily ip injections of PB, PCN, 3-MC, BaP, or vehicle, DBSP (100 mg/kg) was injected iv and was measured in blood and bile over a 40-min period. PB and PCN significantly enhanced plasma disappearance and biliary excretion of DBSP, whereas 3-MC and BaP did not. To determine whether the enhanced plasma disappearance and biliary excretion was entirely due an increase in Mrp2, PCN was also administered ip daily for 4 days to Mrp2-null Eisai hyperbilirubinemic (EHBR) rats and then injected iv with DBSP. PCN significantly increased plasma DBSP disappearance in EHBR rats during early time intervals (2-20 min), but not at later time intervals (25-40 min). PCN did not increase DBSP biliary excretion in EHBR rats, but actually decreased it at later time intervals. In summary, the increase in Mrp2 protein after microsomal enzyme induction is responsible for increased biliary DBSP excretion. Furthermore, the increase in Mrp2 protein after microsomal enzyme induction is not responsible for the enhanced plasma DBSP disappearance at early time points, yet may influence plasma DBSP disappearance at later time points. This study also demonstrates the importance of compensatory hepatic transporters in eliminating DBSP by alternative pathways other than Mrp2.     

Studies on the mechanism of spironolactone protection against indomethacin toxicity

Pretreatment of rats for 4 days with spironolactone (75 mg/kg) increases the LD50 of indomethacin from 13 (12.7–14.5) mg/kg ip to 37 (34–41) mg/kg ip. In an attempt to determine the mechanism by which spironolactone decreases the toxicity of indomethacin, [¹⁴C]indomethacin (8 mg/kg) was administered ip to control and spironolactone-pretreated rats and the concentration of ¹⁴C in various tissues was determined at timed intervals up to 4 hr. The concentration of ¹⁴C in the tissues of the two groups 30 and 60 min after [¹⁴C]indomethacin administration were similar, but at the 2-, 3-, and 4-hr time intervals, the concentration of ¹⁴C was lower in the blood, plasma, lung, heart, spleen, and muscle of the spironolactone-pretreated rats. This indicates that spironolactone enhances the excretion of indomethacin. The mechanism of the enhanced excretion was studied using [¹⁴C]indomethacin administered iv (4 mg/kg) to control and spironolactone-pretreated rats. The amount of ¹⁴C in the plasma and bile was measured. Spironolactone markedly enhanced the plasma disappearance of ¹⁴C and more than doubled the rate of its excretion into the bile. The increased excretion of ¹⁴C into the bile of the spironolactone-pretreated rats was mostly in the form of more water-soluble metabolites. The increased plasma disappearance and biliary excretion of indomethacin is also observed after other microsomal enzyme inducers. Phenobarbital (75 mg/kg) and pregnenolone-16α-carbonitrile (75 mg/kg) produced a similar increase in the plasma disappearance and biliary excretion of indomethacin as did spironolactone, but 3-methylcholanthrene (20 mg/kg) was without effect. Thus, it appears that spironolactone decreases the toxicity of indomethacin by increasing its biotransformation and excretion into the bile.     

Distribution, excretion, and metabolism of butylbenzyl phthalate in the rat

The disposition of butylbenzyl phthalate (BBP), a widely used plasticizer, was evaluated after oral and iv administration to rats. Male Fischer-344 rats were dosed with [14C]BBP at 2, 20, 200, or 2000 mg/kg po or 20 mg/kg iv to determine the effects of dose on rates and routes of excretion. In 24 h, 61-74% of the dose was excreted in the urine and 13-19% in the feces at 2-200 mg/kg. At the 2000-mg/kg dose, 16% of the 14C was excreted in the urine and 57% in the feces. Urinary 14C was composed of monophthalate derivatives (MP: 10-42% of the dose) and glucuronides of these monophthalate derivatives (2-21% of the dose). At 4 h after iv administration of BBP (20 mg/kg), 53-58% of the dose was excreted in the bile of anesthetized rats. No parent compound was found in the bile, but monobutyl phthalate-glucuronide and monobenzyl phthalate-glucuronide (26% and 13% of the dose, respectively) and trace amounts of free monoesters (2% of the dose) and unidentified metabolites (14% of the dose) were present. Although BBP is an asymmetric diester with the potential of forming equal amounts of monobutyl phthalate (MBuP) and monobenzyl phthalate (MBeP), larger quantities of MBuP were formed (MBuP = 44% versus MBeP = 16% of the dose). The half-lives of BBP, MP, and total 14C in blood (20 mg/kg, iv) were 10 min, 5.9 h, and 6.3 h, respectively. This study indicates that BBP is rapidly metabolized and that the major route of excretion of metabolites is biliary. These metabolites are reabsorbed and ultimately eliminated in the urine.     

Pharmacokinetics and tissue distribution of iv injection of polyphase liposome—encapsulated cisplatin（KM—1） in rats

目的:评价多相脂质体顺铂(KM-1)在大鼠体内的药物动力学及组织分布,并与游离顺铂比较。方法:用电感耦合等离子光谱法(ICP-AES)测定给药后大鼠血清及组织中铂的含量。结果:大鼠尾静脉给予4.5mg/kg剂量的KM-1后,血清-时间曲线符合开放三室模型。主要药动参数为:V_c=0.10L/kg,T_(1/2π)=0.3h,T_(1/2α)=3.5h,T_(1/2β)=2.7h,AUC-265mg·h·L~(-1),CL(s)=0.02g·L~(-1)·h~(-1)。多相脂质体顺铂从血清中的消除速率小于游离顺铂。药物在组织中的分布以肝、脾器官中的含量最高。结论:该药物具有一般脂质体的基本特性,在血液循环中停留的时间比游离药物长,且易被网状内皮系统丰富的组织器官吸收。     

Comparison of lymphatic uptake, metabolism, excretion, and biodistribution of free and liposome-entrapped [14C]cytosine beta-D-arabinofuranoside following intraperitoneal administration to rats

Free [14C]cytosine beta-D-arabinofuranoside ([14C]ara-C) was completely absorbed from the peritoneal cavity of thoracic duct-cannulated rats by 6 hr after ip dosing. 14C levels in most tissues were higher at 4 hr than at 12 hr after dosing and were generally undetectable at 24 hr. By 6 hr after treatment only 2% of the dose was recovered in lymph, whereas 90% had been excreted in urine. Liposome entrapment of ara-C reduced the rates at which the drug was absorbed from the peritoneal cavity and excreted in urine while enhancing lymphatic uptake of the drug by more than 10-fold. Radioactivity in plasma and most tissues achieved higher concentrations and persisted for longer periods in rats given liposome-entrapped ara-C than in rats receiving the free drug. Most striking was the localization of 14C-activity in renal and thoracic lymph nodes of rats give liposome-entrapped ara-C, with 300 to 1000-fold higher levels present at 4, 12, and 24 hr after dosing than in corresponding lymph nodes of rats receiving the free drug. The metabolic conversion of ara-C to uracil beta-D-arabinofuranoside (ara-U) was reduced by approximately 3-fold following liposome entrapment of the drug. The enhanced lymphatic uptake and the localization and persistence of ara-C in lymph nodes resulting from liposome entrapment of the drug may be of benefit in treating tumors that metastasize via lymphatic pathways.     

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.     

Biodistribution and metabolism in rats and mice of bucromarone.

The metabolism and disposition of bucromarone, labeled with 14C on the chromone group, has been investigated in C3H mice and Wistar rats. In separate experiments, animals received 4.4 mmol/kg, iv or po, [14C]bucromarone hydrochloride or succinate. More than 90% of the administered radioactivity was excreted in bile, after iv and po administration. Less than 5 min after iv injection, radioactivity concentrated in all tissues, and blood concentration became very low as compared with its initial level. After po administration, no more than 10% of the dose was incorporated in the tissues. The discrepancy between the high biliary excretion and the low tissue and blood concentration after po administration suggested that bucromarone was well absorbed through the gastrointestinal tract; but after liver uptake, drug and its metabolites were excreted in the bile, less than 10% being distributed into the extrahepatic blood. Comparison of the iv and po areas under the plasma 14C-radioactivity concentration-time curves indicated a poor bioavailability of the molecule after po administration. Analysis of the radioactivity content of bile showed that bucromarone was extensively metabolized after both administration routes. Unchanged bucromarone and three main metabolites, monodesbutylbucromarone, didesbutyl bucromarone, and 2-(3-5-dimethyl-4-hydroxybenzoyl) chromone, amounting to 85% of the bile radioactivity, were identified by HPLC and mass spectrometry. These findings are consistent with a dealkylation of the N-dibutyl group, yielding potential pharmacologically active metabolites monodesbutyl and didesbutyl bucromarone.     

Disposition of the radioprotector ethiofos in the rhesus monkey. Influence of route of administration

Plasma concentrations of ethiofos [S-2-(3-aminopropylamino)ethyl phosphorothioic acid, WR-2721] were compared following iv, ip, intraduodenal, and portal administration to the rhesus monkey. Plasma samples were analyzed for ethiofos, free WR-1065, [2-(3-aminopropylamino)ethanethiol], and total material convertible to WR-1065 (total WR-1065). In separate experiments, total radioactivity in plasma was compared following iv, ip, and intraduodenal administration of [14C]ethiofos; excretion of the radiolabel was measured in urine and in feces. Intraduodenal administration of unlabeled ethiofos rarely gave measurable levels of unchanged drug in plasma. In contrast, intraduodenal administration of [14C]ethiofos produced an average AUC for total radioactivity that was 62% of that for a 10-min iv infusion of [14C]ethiofos. Urinary excretion of radioactivity following iv and intraduodenal administration of [14C]ethiofos was 78.9 +/- 14.0% and 43.8 +/- 12.4%, respectively, whereas 1.9 +/- 0.5% and 9.7 +/- 6.3% was excreted in feces. After an ip dose of either labeled or unlabeled ethiofos, absorption of the dose was prolonged, but AUC values for total radioactivity or ethiofos and total WR-1065 were similar to those observed after the corresponding 10-min iv experiments. For either iv or portal routes, increases in ethiofos AUC values were observed for the same total dose when the infusion rate was increased from 1.25 to 15 mg/kg/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical and morphological studies on the percutaneous uptake of [14C] ethylenediamine in the rat

Male Wistar rats were exposed to aqueous [14C]ethylenediamine (EDA) solutions (10, 25, or 50%) percutaneously over a 7 x 7 cm area on the back with occlusion for 24 h. For each rat dosed, three types of studies were conducted: (1) plasma kinetics, (2) material balance, and (3) histological evaluation, including autoradiography of the skin sample from the dosing area. Adequate kinetic measurements were obtained only from animals treated with 25 and 50% EDA, but not from the 10% treatment group, due to analytical limitations. The uptake of [14C]EDA percutaneously by the rat was relatively slow in comparison with uptake following peroral or endotracheal administration. The absorption of EDA by the animals was estimated to be greater than 61, 55, and 12%, respectively, for the 50, 25, and 10% treatment groups. A large portion (11-32%) of the dose was left on/in the dosing area. Urinary excretion was the predominant route for the disposition of EDA. The recovery of the administered dose was low (70-83%), possibly due to volatilization of EDA from the skin during dosing and holding. Histologic examination of skin sections (dosing areas) revealed a normal, intact epidermis in rats dosed with 10% EDA, but full-thickness epidermal necrosis in rats dosed with 25% or 50% EDA solutions. The damage of the epidermis apparently enhanced the penetration of EDA. Autoradiographic preparations revealed a concentration of the [14C]EDA radiolabel over the keratin layer and hair shafts.     

Disposition and tissue distribution of angiopeptin in the rat.

The disposition and tissue distribution of angiopeptin, a long-acting octapeptide analogue of somatostatin, were studied in rats following single iv and sc administration of the drug. Similar plasma levels and excretion values of angiopeptin were observed by using radioimmunoassay and radiolabeling techniques. Angiopeptin was absorbed fairly rapidly, with a mean peak plasma level of 25 +/- 4.1 ng/ml at 10-15 min after administration. The kinetics of angiopeptin following sc administration closely resembled those following iv administration due to rapid absorption. The pharmacokinetics of angiopeptin can be described by a two-compartment model. The plasma half-life of the drug ranged from 2.6-2.9 hr when administered sc and 1.98-2.5 hr when given iv. Distribution of angiopeptin was rapid, with the highest concentration appearing in the liver. Half-lives in the liver and bile were short. Most of the drug was excreted in the feces via the bile, while approximately 10% was excreted in the urine. Angiopeptin was also found to be secreted in the saliva. TLC and HPLC of blood, urine, feces, and bile samples did not reveal the presence of any metabolites. In conclusion, the in vivo fate of angiopeptin is characterized by little or no hepatic metabolism and rapid biliary excretion.