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.     

Metabolic disposition and irreversible binding of 1-phenylcyclohexene in rats

The metabolic disposition of l-[¹⁴C]phenylcyclohexene ([¹⁴C]PC) was examined in rats after ip or iv drug administration. Radioactivity, which was accumulated by various organs, peaked within 30 min after ip administration of [¹⁴C]PC (0.21 mg/kg). A significant amount of this radioactivity was not extractable by repeated methanol extractions, indicating irreversible binding of [¹⁴C]PC metabolite(s) to tissue proteins. Following iv administration of [¹⁴C]PC (0.42 mg/kg), [¹⁴C]PC concentrations in blood declined biphasically with time; the blood elimination half-life of [¹⁴C]PC is 77 min. About 83% of the dose given was excreted in urine and feces within 54 hr of administration. About 35% of the dose was excreted in the bile in 1 hr. At least four [¹⁴C]PC metabolites were detected in the urine or bile. The bulk of the urinary radioactivity was composed of metabolites since less than 6% of [¹⁴C]PC given was excreted unchanged in the urine.     

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)     

Effect of sodium salicylate on the fate of warfarin in the rat

Salicylate (88.9 mg/kg, po) decreased the blood level of radioactivity emanating from [¹⁴C]warfarin (1 mg/kg, iv and po) during the 24 hr following drug administration, reduced the area under the blood radioactivity vs time curve, and shortened the half-life for elimination of radioactivity from the blood. During the first 6 hr after drug administration, salicylate increased the biliary excretion of radioactivity, which resulted in enhanced fecal excretion of warfarin and its metabolites. Salicylate administration initially increased and later decreased the amount of radioactivity in the liver, and increased the proportion of warfarin metabolites to unchanged warfarin in this organ. It did not affect the proportion of unchanged warfarin to metabolites in the blood, bile and urine, or the total amount of radioactivity excreted during 48 hr in the urine and feces. In vitro, salicylate decreased the binding of [¹⁴C]warfarin to rat serum proteins in a linear manner. It is concluded that, in the rat, salicylate competes with warfarin for serum protein binding sites, thereby facilitating its uptake by the liver. Second, through a combination of its choleretic action and effect on membrane transport, salicylate enhances the biliary excretion of warfarin and its metabolites, thus accounting for the decreased concentration in the blood and lowered antiboagulant action.     

Studies on the pharmacokinetics and metabolism of 4-chlorodiphenyl ether in rats

The metabolic disposition of 14C-labeled 4-chlorodiphenyl ether ([14C]4-CDE) was examined in rats following iv administration of a single dose (850 nmol/kg). [14C]4-CDE decayed rapidly from the blood since no unchanged [14C]4-CDE was detected in the blood beyond 2 hr after [14C]4-CDE administration. The dispositional kinetics of [14C]4-CDE in rats were best described by a two-compartment open pharmacokinetic model. Total radioactivity was excreted slowly from rats; about 41% and 33% of the administered dose were excreted into the urine and feces, respectively, within 1 week after chemical administration. About 5% of the total radioactivity administered to rats was excreted into the bile in 1 hr. The bulk of the radioactivity in the excreta was due to the presence of [14C]4-CDE metabolites. 14C-labeled 4'-hydroxy-4-CDE was the major metabolite and accounted for at least 90% of the radioactivity in the urine. The metabolic conversion of [14C]4-CDE to 14C-labeled 4'-hydroxy-4-CDE was corroborated by in vitro studies with liver microsomes of rats. In addition, [14C]4-CDE was converted by liver microsomes to reactive metabolites which bound irreversibly to microsomal protein. An arene oxide is suggested as the intermediate metabolite in the biotransformation of [14C]4-CDE by rats.     

Distribution, excretion, and metabolism of nitro-p-phenylenediamine in rats

The distribution, excretion, and metabolism of nitro-p-phenylenediamine, a constituent of hair dye, was studied after administration of [14C]nitro-p-phenylene-diamine (2.6 mg/30 microCi/kg) to male rats. After intraperitoneal administration, 37.4% of the radioactivity administered was excreted in the urine and 54.3% in the feces within 24 h. After intravenous administration, 42.2% of the radioactivity was excreted in the bile within 24 h. The highest concentration of radioactivity in tissues was found at 1 h, except in the small and large intestines, followed by a rapid decrease in concentration. Only small amounts of radioactivity were found in the tissues 48 h after administration. Some of the radioactive materials in the urine were separated by thin-layer chromatography and identified as N1,N4-diacetyl-2-amino-p-phenylenediamine, N4-acetyl-2-nitro-p-phenylenediamine, and unchanged nitro-p-phenylenediamine.     

Intestinal absorption, intestinal distribution, and excretion of (14C) labelled hyoscine N-butylbromide (butylscopolamine) in the rat

Butylscopolamine was labelled with ¹⁴C and its gastrointestinal absorption, biliary and urinary excretion, enterohepatic circulation and gastrointestinal distribution were examined in anaesthetized rats. Biliary excretion was the main elimination route of intra-portally administered [¹⁴C]butylscopolamine, with 42% of the dose recovered in the bile during 12 h. About 6% of the radioactivity administered orally as [¹⁴C]butylscopolamine was excreted in the bile and 1.2 % in the urine during 24 h, which indicates poor gastrointestinal absorption of butylscopolamine in the rat. When collected radioactive bile was readministered intrajejunally, only about 7% of the radioactivity was recovered in bile and urine during 12 h, which suggests that only a small fraction of butylscopolamine and its metabolites engage in an enterohepatic circulation. After oral administration of [¹⁴C]butylscopolamine, radioactivity was found to accumulate in the wall of the distal small intestine, and about 20% of the dose was found in this tissue 24 h after drug administration. As a result, local anti-acetylcholine effects of butylscopolamine might be expected.     

The metabolism and excretion of carbovir, a carbocyclic nucleoside, in the rat

The metabolism and disposition of carbovir [(1R-cis)-2-amino 1,9-(4-(hydroxymethyl)-2-cyclopenten-1-yl)-6H-purin-6-one], an antiviral agent, was examined in rats using an isolated perfused liver, and in vivo following iv and po administration at two dosing levels. HPLC analysis of perfusate and bile after perfusion of the isolated liver with racemic (+/-)[8-3H]carbovir showed conversion to two major metabolites. The major component in the bile was shown to be a glucuronide conjugate of carbovir. The perfusate contained a single major component that was isolated and identified as the 4'-carboxylic acid derivative. In vivo excretion balance studies were conducted with [8-14C](-)-carbovir using four animals in each dosing group. Following iv administration at 10 mg/kg doses, the majority of the dose (77%) was excreted in the urine. At 60 mg/kg iv dosing, this value dropped to 42% (the remainder appearing in the feces). With po administration at both doses, the bulk of the dose (41-61%) was excreted in the feces. HPLC profiling of the urine showed that in all cases, most of the radioactivity was accounted for as carbovir and the 4'-acid metabolite. This metabolite accounted for up to 25% of the administered dose following 60 mg/kg iv administration, and less than 3% following 10 mg/kg po dosing. A second urinary metabolite accounting for up to 5% of the dose also was seen in all samples. This was isolated and identified as the trans-diastereomer of the 4'-acid (resulting from epimerization at the 4' position).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism and disposition of the flame retardant tris(2,3-dibromopropyl)phosphate in the rat

The metabolism and disposition of the flame retardant, tris(2,3-dibromopropyl)phosphate (Tris-BP), were studied after po and iv administration of the 14C-labeled compound to the male rat. Tris-BP was readily absorbed from the gastrointestinal tract and rapidly distributed throughout the body. The distribution and excretion of Tris-BP derived radioactivity were similar after either po or iv administration. The only effects of route of administration on tissue distribution were slightly higher concentrations in liver after po administration and in lung after iv administration. The initial elimination of Tris-BP derived radioactivity in urine, feces, and as CO2 accounted for approximately 50% of the dose in 24 hr. An analysis of Tris-BP derived radioactivity remaining in the tissues one day after administration indicated that most of the radioactivity in all tissues was in the form of various metabolites rather than the parent compound. The terminal clearance of Tris-BP derived radioactivity from most of the tissues studied was best described by a single component exponential decay with a half-life of approximately 2.5 days. Clearance from liver and kidney was somewhat slower having a half-life of approximately 3.8 days. Approximately 33% of the radioactivity excreted in urine and approximately 50% of the radioactivity excreted in bile were identified by cochromatography with synthesized standards on high performance liquid chromatography (HPLC). Six metabolites and a trace of the parent compound were identified in urine and bile by this method. The six metabolites products of dealkylation and dehydrobromination of the parent compound. The metabolites of Tris-BP isolated from urine and bile were also formed in vitro by NADPH-dependent microsomal enzymes from rat liver. The soluble enzymes from liver metabolized Tris-BP to at least three unidentified polar metabolites.     

Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor,in dogs: Identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5?mg?kg^?1 dose of [¹⁴C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72?h. Male bile duct-cannulated dogs excreted a mean of ～56% of the dose in bile, ～11% in feces, and ～25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [¹⁴C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.     

Metabolic disposition of trimetrexate, a nonclassical dihydrofolate reductase inhibitor, in rat and dog

The metabolic disposition of trimetrexate, a nonclassical inhibitor of dihydrofolate reductase, was characterized in the rat. After iv administration of 1.2 mg/kg [14C]trimetrexate (as the glucuronate), recovery of total radioactivity in urine and feces through 144 hr was greater than 96% of dose. Trimetrexate was extensively metabolized, with only 13% of the dose excreted unchanged in urine and bile. Profiling of biliary and urinary radioactivity showed three components and unchanged drug accounted for the majority of excreted radioactivity (75% of dose). Tandem mass spectral analysis of one urinary component suggested trimetrexate had undergone N-dealkylation and oxidation to 2,4-diamino-5-methyl-6-quinazolinecarboxylic acid. Structural assignment for this metabolite was confirmed by comparison to authentic reference material. Mass spectral analysis of a second component gave a quasimolecular ion (MH)+ at m/z 532 with a key fragment ion at m/z 356 (MH-176)+, characteristic of a glucuronide conjugate. The proton NMR spectrum of this component was consistent with expectations for a glucuronide conjugate of 4'-O-desmethyl trimetrexate. Possible formation of a sulfate conjugate was explored by co-administration of unlabeled trimetrexate with [35S]sulfate to rats. A 35S-labeled component was excreted in urine, which co-eluted with the third major urinary 14C-labeled component observed in the first experiment. Mass spectrum of this component was consistent with the structure of trimetrexate-4'-O-desmethyl sulfate. In dogs, the disposition of trimetrexate was examined using stable isotope-labeled material. The dose was 10 mg/kg administered iv as a 1:1 mixture of 13C2, 15N-labeled and unlabeled trimetrexate glucuronate.(ABSTRACT TRUNCATED AT 250 WORDS)     

雷公藤甲素在大鼠体内过程的研究

雷公藤甲素具有抗肿瘤、抗炎和免疫抑制作用,能迅速由胃肠道吸收,但并不完全。本实验研究了该药口服和静注给药途径的分布和排泄,结果表明:口服和静注后,药物在体内的分布和消除速率大体相似,均以肝中浓度为最高,依次为脾、肺、肾、肠、心和脑,体内消除较缓慢。血浆蛋白结合率为64.7%。24d内,口服后尿粪总排泄量为给药量的67.5% ,其中粪占52.4%;静注后为61.9%,粪占25%。24h内胆汁排泄为6.73%。提取尿、粪和胆汁经TLC、放射性测定及放射自显影分析,表明以原药排泄为主和部分代谢物。     

Metabolic disposition and irreversible binding of phencyclidine in rats

The metabolic disposition of [¹⁴C]phencyclidine ([¹⁴C]PCP) was examined in rats after intratracheal, ip or iv drug administration. [¹⁴C]PCP absorption by the lung was related to time biphasically after intratracheal administration. At 1 hr after ip administration of [¹⁴C]PCP (1.8 mg/kg), the concentration of radioactivity in various tissues decreased (in descending order) in the liver, fat, kidney, lung, testes, spleen, heart, and brain. High levels of radioactivity were also detected in the urine and feces, but not in the blood. The radioactivity accumulated by the liver, lung, and kidney was only partially removed by repeated extraction with 80% methanol, indicating the in vivo formation of PCP reactive metabolite which bound with protein irreversibly. Incubation of [¹⁴C]PCP with rat liver microsomes corroborated that a PCP reactive metabolite was formed. Although hepatic benzpyrene hydroxylase activity decreased significantly after rats were pretreated with PCP, neither microsomal cytochrome P-450 content nor aniline hydroxylase and p-chloro-N-methyl-aniline demethylase activities in lung, liver, and kidney were altered. After a single iv dose of [¹⁴C]PCP (0.9 mg/kg), biliary radioactivity peaked at about 30 min. Hydroxylated PCP and corresponding glucuronides represented the bulk of the biliary radioactivity. When radioactive bile from a rat pretreated with [¹⁴C]PCP was administered to a recipient rat intragastrically, radioactivity was found in the bile, indicating enterohepatic recycling of PCP.     

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate in rats, dogs and monkeys

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) were studied in rats, dogs and monkeys after administration of [14C]-MN-1695. MN-1695 was found to be well absorbed from the small intestine after oral administration in all species examined. Plasma level of unchanged MN-1695 reached a maximum at 1 to 4 h after oral administration of [14C]-MN-1695 in rats, dogs and monkeys. The mean elimination half-life of unchanged MN-1695 from plasma was about 3, 4 and 50 h in rats, dogs and monkeys, respectively. Tissue levels of radioactivity after oral administration of [14C]-MN-1695 in rats indicated that [14C]-MN-1695 was distributed throughout the body and the radioactivity in tissues disappeared with a rate similar to that in plasma. A stomach autoradiogram after intravenous administration of [14C]-MN-1695 in the rat revealed the radioactivity localized in the gastric mucosa where MN-1695 was assumed to exert its pharmacological activity. In pregnant rats, [14C]-MN-1695 was distributed to the fetus with levels similar to maternal blood levels. After oral administration of [14C]-MN-1695 in rats, 39 to 46% of the dose was excreted into the urine and 50 to 63% of the dose into the feces, within 96 h. In dogs, about 40% of the dose was excreted into the urine and about 50% of the dose into the feces, within 6 days after oral administration. In monkeys, within 14 days after oral administration, about 60 and 30% of the dose were excreted into the urine and feces, respectively, and the main excretion route was the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of a purified diet and route of administration on the metabolism and disposition of estradiol in B6C3F1 mice

The metabolism and disposition of [6,7-3H]estradiol ([3H]E2) given by gavage (po) or intravenously (iv) were examined in female B6C3F1 mice fed either the purified AIN-76A (AIN) or cereal-based NIH-07 (NIH) diet for a period of 8 weeks prior to treatment with E2. Initially, 40.6 Ci of [3H]E2 was given iv to each mouse. Subsequently, 45.6 Ci of [3H]E2 was given po to the same mice. Samples of blood, urine, and feces were obtained during a 48-hr period after each dosing. Total radioactivity was determined for each sample. Urine and plasma samples were analyzed by HPLC, and the radiolabeled metabolites were tentatively identified and quantified. Statistical comparisons were made of the effects of diet, route of administration, and interactions among groups. Analysis revealed: 1) greater fecal than urinary excretion of radioactivity regardless of route of administration or diet fed, 2) more radioactivity excreted in the urine of AIN-fed than in NIH-fed mice, significantly different only after iv administration (p less than 0.02), and 3) a greater feces:urine ratio of excreted radioactivity following iv than po administration and from NIH-than AIN-fed mice. Metabolite profiles showed: 1) no differences in urine due to route of administration, 2) estriol conjugates dominated urinary metabolites, 3) accumulation of radioactive material in plasma that apparently was tritiated water, with more rapid accumulation of tritiated water after po than iv administration, 4) relatively more plasma estradiol-17-glucuronide, estriol-3-sulfate, and estriol in po- than in iv-treated mice, 5) estradiol-3, 17-sulfate in plasma of iv- but not po-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition of 3,3′-dichlorobenzidine in the rat

The disposition of the carcinogen 3,3′-dichlorobenzidine (DCB) was studied in the male rat following oral administration. [¹⁴C]DCB was well absorbed by the rat with the maximum plasma radioactivity levels being found within 8 hr after dosing. The radioactivity was well distributed in the tissues 24 hr after administration with the highest levels found in the liver, followed by kidney, lung, and spleen. Repeated administration (six doses) of [¹⁴C]DCB to animals did not result in a substantial accumulation of ¹⁴C in the tissues. The elimination of radioactivity from the plasma, liver, kidney, and lung was biphasic showing an initial rapid decline (half-lives 1.68, 5.78, 7.14, and 3.85 hr, respectively) followed by a slower disappearance phase (half-lives 33.0, 77.0, 138.6, and 43.3 hr, respectively). Approximately half of the total ¹⁴C in the liver and kidney was covalently bound to cellular macromolecules 72 hr after dosing. [¹⁴C]DCB-derived radioactivity was extensively excreted by rats, mainly via the feces. Approximately 23–33% of the administered dose was recovered in the urine and 58–72% in the feces of rats within 96 hr. More than 65% of the administered ¹⁴C was eliminated in the bile of bile duct-cannulated rats within 24 hr after dosing. The radioactivity excreted in the urine and bile was primarily in the form of free (urine 71.2%, bile 25.5%) and conjugated (urine 19.6%, bile 57.9%) metabolites of DCB. Thus DCB is readily absorbed following oral administration, and then metabolized and excreted mainly via the feces.     

The metabolic disposition of C-labelled carmoisine in the rat after oral and intravenous administration

The absorption, distribution and excretion of the red azo dye carmoisine (Ext. D & C No. 10) was studied in male rats. [14C]Carmoisine was administered in a dose of 200 mg/kg (25 microCi) by gavage or in the same dose (200 mg/kg; 3 microCi) by intravenous injection, and radioactivity was measured in blood, tissue, faeces and urine at different times after dosing. After oral administration of the dye, no radioactivity was detected in the brain, adipose tissue, muscle, testes, spleen or lung, and recovery of the administered activity in faeces and urine was almost complete by 32 hr. The radioactivity profile of the blood indicated rapid but poor absorption of [14C]carmoisine, a maximum radioactivity content corresponding to 0.01% of the dose per ml of blood being reached within 10 min. The decay curve for 14C radioactivity in the blood after iv injection of [14C]carmoisine indicated rapid distribution to the tissues and could be described in terms of a two-compartment mathematical model. The highest levels of radioactivity occurred in the gastro-intestinal tract and liver after the injection but after 24 hr no radioactivity was detectable in these or other tissues. All the radioactivity was recovered in the faeces and urine in the 24 hr following iv injection, the 79% of the dose present in faeces indicating active excretion of the dye and its metabolites in the bile and poor reabsorption from the intestine. The bioavailability of [14C]carmoisine, calculated from the blood-radioactivity curves after oral and iv administration, was less than 10%.     

Disposition and metabolism of letosteine in rats

The metabolism and disposition of letosteine, labeled either with 14C or 35S, has been investigated in Sprague-Dawley rats. In separate experiments, rats received 20 mg/kg, iv or orally, [14C]letosteine or [35S]letosteine. Radioactivity was rapidly excreted, mainly in urine, after iv and oral administration. Recovery of radioactivity from 0-72-hr excreta averaged 95% after both routes of [14C]letosteine administration, whereas only 50% was recovered when [35S]letosteine was administered. 14CO2 accounted for about 7.3% (iv) and 5.1% (po) of the dose of [14C]letosteine. Comparison of the iv and oral areas under the plasma 14C radioactivity concentration-time curves suggested that oral absorption of letosteine was complete. Analysis of the radioactivity content of urine showed that letosteine undergoes rapid and extensive metabolism. Several metabolites were identified by TLC, HPLC, and MS. The findings are consistent with a splitting of the ester group of letosteine and subsequent cleavage of the thiazolidinyl ring, yielding cysteine, hypotaurine, taurine, and inorganic sulfate. The metabolite derived from the side chain was identified in the urine as 3-(hydroxycarbonylmethylthio)propanoic acid. It undergoes further oxidation into sulfoxide and sulfone derivatives, which are also present in the urine.     

Di-(2-ethylhexyl)adipate: absorption, autoradiographic distribution and elimination in mice and rats

Whole-body autoradiography was used to study the tissue distribution of the plasticizer di-(2-ethylhexyl) adipate (DEHA), labelled in the acid [carbonyl-14C] or alcohol [2-ethylhexyl-1-14C]moiety, after iv or ig administration to male mice and rats and pregnant mice. With both DEHA preparations, during the first 24 hr after administration high levels of radioactivity were observed particularly in the body fat, liver and kidneys (after iv and ig administration) and in the intestinal contents (after ig administration) of both species. After administration of [carbonyl-14C]DEHA, radioactivity was also registered in the adrenal cortex, corpora lutea of the ovary, bone marrow, forestomach mucosa, salivary glands and Harder's gland in both species. [2-ethylhexyl-1-14C]DEHA derived radioactivity was found in the bronchi in male mice. Radioactivity was observed in the foetal liver, intestine and bone marrow during the first 24 hr after iv or ig administration of [carbonyl-14C]DEHA to pregnant mice. There was very little accumulation of [2-ethylhexyl-1-14C]DEHA in the mouse foetus but some was found in the urinary bladder, liver and intestinal contents as well as in the amniotic fluid. In an absorption/elimination study in rats of doses of 25 microCi/kg body weight of [14C]DEHA administered ig, dissolved in corn oil or dimethylsulphoxide, blood levels of radioactivity increased somewhat faster and were two or three times higher when DMSO was the vehicle indicating poor absorption of DEHA from the corn oil solution which more accurately reflects human contact with DEHA. Little radioactivity from [carbonyl-14C]DEHA was recovered in the bile, whereas [2-ethylhexyl-1-14C]DEHA was excreted in the bile in significant amounts particularly when DMSO was the vehicle. There was evidence of enterohepatic circulation of DEHA. Radioactivity was also excreted in the urine. As shown by autoradiograms obtained 4 days after the administration of [14C]DEHA there was no retention of DEHA and/or its metabolites in the tissues of mice.     

The fate of trimethylamine in the rat

The metabolism and excretion of [14C]-trimethylamine has been investigated in seven strains of rat. Over 75% of the administered radioactivity was excreted via the urine within the first day, with up to 9% in the faeces. At this dose level (15 mg/kg body wt) N-oxidation was the major metabolic pathway encountered (45% excreted dose) whilst demethylation was only of minor importance (3%). The remaining compound was excreted unchanged. No significant differences were observed between the strains studied.