Toxaphene: accumulation in the adrenal cortex and effect on ACTH-stimulated corticosteroid synthesis in the rat

Uptake and distribution of [14C]toxaphene was studied in the adrenals of rats using whole-body autoradiography. An accumulation of radioactivity was seen in the adrenal cortex (zona fasciculata) 1-24 h after a single gavage of [14C]toxaphene (16 mg/kg b.w.). In in vitro studies toxaphene was found to inhibit ACTH-stimulated corticosterone synthesis in the cultured rat adrenocortical cells (IC50 2.8 X 10(-5) M). Moderate but significant inhibition (P less than 0.001) of ACTH-stimulated corticosterone synthesis was also observed in the adrenocortical cells isolated from rats after a prolonged exposure (5 weeks) to low levels (1.2 ppm) of toxaphene in feed. The results indicate a direct adrenotoxic effect of toxaphene.     

Disposition of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally, and topically and in guinea pigs dosed topically

To determine the metabolic disposition of [14C]-2-mercaptobenzothiazole (MBT) and [14C]-2-mercaptobenzothiazole disulfide (MBTS), male and female rats were dosed topically. Topical doses were 36.1 micrograms/animal for [14C]MBT and 33.6 micrograms/animal for [14C]MBTS. Although more MBT passed through the skin than MBTS and although, relative to rats, guinea pigs absorbed a greater percentage of the dose (33.4% compared to 16.1-17.5% of the MBT and 12.2% compared to 5.94-7.87% for MBTS), the disposition of radioactivity derived from the two compounds was similar. Washing of the skin removed more of the radioactivity from guinea pigs than from rats. For both sexes of rats dosed intravenously with [14C]MBT (0.602 mg/kg) or [14C]MBTS (0.571 mg/kg), disposition of the compounds was similar. In 72 h, 90.9-101% of the dose appeared in the urine and 3.79-15.1% in the feces. At this time, a small portion of the administered radioactivity (1.52-1.96% of the dose) remained associated with erythrocytes. Oral dosing of rats for 14 d with unlabeled MBT (0.510 mg/kg.d) prior to a single dose of [14C]MBT (0.503 mg/kg) or with unlabeled MBTS (0.521 mg/kg.d) prior to a single dose of [14C]MBTS (0.730 mg/kg). For both sexes, disposition of the compounds was similar. At 96 h after dosing, a small portion of the administered radioactivity (1.20-1.69% of the dose) remained associated with erythrocytes, most of which was bound to the membranes. For both compounds and sexes, 60.8-101% of the radioactivity administered appeared in the urine and 3.46-9.99% in the feces in 96 h. At the time, only trace amounts of radioactivity remained in tissues other than blood. Of these tissues, thyroid contained the highest concentration. In the urine, there was a detectable MBT or MBTS, but there were two metabolites, one of which was identified as a thioglucuronide derivative of MBT. The other was possibly a sulfonic acid derivative of MBT. In conclusion, there were similarities in absorption, distribution, and metabolism of [14C]MBT and [14C]MBTS in rats and in guinea pigs, indicating that [14C]MBTS was readily converted to [14C]MBT.     

Studies on the tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea in mice.

The tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea has been studied in mice. A large part of the injected N-[14C]ethyl-N-nitrosourea radioactivity was found to be exhaled as 14CO2. Whole-body autoradiography showed evenly distributed radioactivity in most tissues shortly after the administration of N-[14C]ethyl-N-nitrosourea which probably is due to the homogeneously distributed substance and the non-enzymatically formed ethyl-carbonium ions which have reacted with the tissues. The blood-brain barrier seemed to have a capacity to partially prevent the uptake of the substance in the central nervous system. A high radioactivity was observed in the liver, which may imply that N-[14C]ethyl-N-nitrosourea is enzymatically decomposed in this tissue. An observed labelling of kidneys may be connected with urinary excretion of radioactivity. The radioactivity in the liver and kidney decreased at later survival intervals and a distribution pattern appeared, which was characterized by a labelling of tissues with a high protein or steroid synthesis and of fat containing tissues. The distribution pattern corresponded to the one seen after the administration of [14C]acetaldehyde and is probably due to normal biosynthetic incorporation of radioactivity in the 2-carbon pool. Pretreatments with pyrazole, nialamide and diethyldithiocarbamate caused a marked inhibition of the exhalation of 14CO2 and of the incorporation of radioactivity in the liver. This effect may be directed towards the decomposition of N-[14C]ethyl-N-nitrosourea itself, but an effect on the metabolism of formed 2-carbon fragments is also possible. The incorporation of radioactivity in other tissues was not influenced by the pretreatments.     

Disposition and metabolism of the novel antihypertensive agent alacepril in rats

Disposition and metabolism of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) in rats were studied and compared to those of 1-[(S)-3-mercapto-2-methylpropanoyl]-L-proline (captopril), using 14C-labeled compounds. Some tissue homogenates and plasma of rats were incubated in vitro with [14C]alacepril or [14C]captopril at the concentration of 50 nmol/ml. For in vivo studies, radioactive agents were orally or intravenously administered to rats in doses of 46 mumol/kg (18.7 and 10 mg/kg for alacepril and captopril, respectively) or 460 mumol/kg. In vitro studies revealed that [14C]alacepril is converted to captopril via desacetyl-alacepril (DU-1227) in the liver, kidney and intestine homogenates, but not in the lung homogenate and plasma where deacetylation alone occurred. DU-1227 and captopril formed were found to be partly bound with endogenous -SH compounds i.e. cysteine, glutathione and probably, protein. 1 h after oral administration of [14C]alacepril, plasma levels of total radioactivity reached a maximum of 8 nmol/ml and disappeared with t1/2 of 2.6 h. [14C]Captopril radioactivity was maximum (13 nmol/ml) at 40 min with the disappearance t1/2 of 1.9 h. Similarly to total radioactivity, levels of radioactivity unbound and bound to plasma protein after [14C]alacepril were lower at maximum and disappeared more slowly than those after [14C]captopril. After oral administration of [14C]alacepril, DU-1227, captopril and mixed disulfides of captopril with cysteine and glutathione were detected in the plasma unbound fraction. The three metabolites except for DU-1227 were commonly detected after [14C]captopril.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fish bile analysis: a possible aid in monitoring water quality

In vivo exposure of rainbow trout (Salmo gairdneri) to [¹⁴C]-carbaryl, [¹⁴C]-3-trifluoromethyl-4-nitrophenol, and [¹⁴C]-DDT have demonstrated that the concentration of radioactivity from these compounds in bile is much greater than that in the surrounding water. Since, with several of the compounds, the bile-to-water ratios rise to greater than 1000 in a 24-hr exposure period, the use of biliary sampling may be of potential use as an aid in monitoring water quality by taking advantage of this bioconcentration mechanism.     

Blood level, distribution, metabolite pattern and excretion of [14C]alinidine in mice and rats

Following oral and intravenous administration the absorption, distribution, metabolite pattern and excretion of [14C]alinidine, a drug with specific bradycardic efficacy, was studied in mice and rats. [14C]alinidine was rapidly and extensively absorbed. The distribution of radio-labelled drug over the entire animal body was rapid as indicated by blood level curves as well as by whole body autoradiography. In both species radioactive compounds were eliminated from blood with half-lives ranging from 5.6 h to 7.4 h. More than 50% of the renally excreted radioactivity was a uniform substance behaving in in TLC and HPLC experiments like the drug administered. From rat urine this compound could be identified as [14C]alinidine using mass spectrometry. In mice and rats no definite substance with clonidine-like chromatographic properties was found. Biliary excretion was demonstrated in both species. The renal portion of the total radioactivity elimination was 67.2-70.1% of the dose administered in mice and 68.1-85.1% in rats. Total excretion was 85.1-101.3% of radioactivity given and was complete 3-4 days after [14C]alinidine administration. No significant differences in pharmacokinetic behavior in mice and rats could be found.     

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%.     

In vitro biotransformations of [14C]captopril in the blood of rats,dogs and humans

The biotransformations of captopril (CP), an orally effective antihypertensive agent, were studied in vitro in whole blood, plasma, and washed blood cells of rats, dogs and humans, using ¹⁴C-labeled CP. Thin-layer chromatographic profiles of the radioactivity extracted into methanol showed that, in plasma and whole blood, [¹⁴C]CP was biotransformed to its disulfide dimer, [¹⁴C]CP-CP, and to two other compounds identified as the [¹⁴C]CP-glutathione and [¹⁴C]CP-l-cysteine mixed disulfides. After incubation with either washed blood cells or a saline control, most of the [¹⁴C]CP remained unchanged. Since not all of the radioactivity in the biological samples could be extracted, the nature of the unextracted radioactivity was investigated. Results obtained using methanol extraction, ultrafiltration and acid precipitation techniques indicated that [¹⁴C]CP was extensively and covalently bound to plasma proteins. In human plasma, [¹⁴C]CP was shown to be bound primarily to albumin through covalent disulfide bonds. In the plasma of all three species, these covalent disulfide bonds could be cleaved by glutathione or l-cysteine, resulting in the formation of mixed disulfides, or by dithiothreitol, resulting in the release of [¹⁴C]CP. The behavior of CP in vitro in blood was qualitatively similar to that reported for other endogenous and xenobiotic sulfhydryl compounds and was consistent with the results obtained from in vivo studies with CP.     

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 absorption, tissue distribution and excretion of di-n-octyltin dichloride in rats

In this study the absorption, tissue distribution and excretion of 14C-labeled di-n-octyltin dichloride ([14C]DOTC) in rats were investigated after oral and intravenous (i.v.) administration. Although after i.v. administration with 1.2 mg [14C]DOTC/kg body weight the tissue radioactivity was about 3-4 times higher than after oral administration with 6.3 mg [14C]DOTC/kg body weight, the relative tissue accumulation was found to be the same after the oral and i.v. dosage. The highest amount of radioactivity was found in liver and kidney, and to a lesser degree in adrenal, pituitary and thyroid glands. The lowest activity was recovered from blood and brain. No selective accumulation was observed in thymus, although it has been reported that thymus atrophy is the most sensitive parameter of DOTC toxicity in rats. For all tissues a time dependent decrease in radioactivity was found, except for kidney. The excretion of radioactivity in feces and urine was determined after a single i.v. or oral dose of 1.2 and 2 mg [14C]DOTC, respectively. After i.v. administration most of the radioactivity was excreted in the feces which was characterized by a biphasic excretion pattern. In orally treated rats more than 80% of the radioactivity was already excreted in the feces during the first day after administration. This indicated that only a small part of the DOTC was absorbed, which was calculated to be approximately 20% of the dose. Similar half-life values of 8.3 and 8.9 days were obtained from the fecal excretion of radioactivity after the i.v. and oral administration, respectively. The urinary excretion of radioactivity appeared to be independent of the body burden, since the daily amount of radioactivity excreted in urine was nearly the same independent of the route of administration as well as the time after administration.     

Transfer of some carboxylic acids in the olfactory system following intranasal administration

The uptake of [14C]benzoic acid, 4-chloro[14C]benzoic acid, [3H]phthalic acid and [14C]salicylic acid in the nasal passages and brain was determined following a unilateral intranasal instillation in mice. An uptake of radioactivity from the nasal mucosa to the ipsilateral olfactory bulb was observed up to 4 h after administration following intranasal instillation of these carboxylic acids whereas the level was low in the contralateral olfactory bulb. Autoradiography of mice given [14C]benzoic acid and [14C]salicylic acid by intranasal instillation showed a preferential localization of radioactivity in the axonal and glomerular layer of the olfactory bulb 1 h after the administration. Four hours after administration the radioactivity was present as a gradient from the axonal layer towards the center of the olfactory bulb. Pretreatment of mice with a compound known to damage the olfactory neuroepithelium resulted in a decreased uptake of [14C]benzoic acid in the olfactory bulb. Thin layer chromatography of supernatants from the ipsilateral olfactory bulbs of mice given [14C]benzoic acid by nasal instillation indicated that the radioactivity in the bulbs represented unchanged compound. These results suggest that there is a transfer of some aromatic carboxylic acids in the olfactory pathways.     

Metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline in the male rat

The metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was studied in the male rat using the radiochemical labels 14C and 3H at positions 2 and 5 of the molecule, respectively. Adult male Fischer 344 rats were administered [2-14C]IQ or [5-3H]IQ by oral gavage at dose levels of 20 or 40 mg/kg body weight. Rats were also given [2-14C]IQ in the diet at a dose level of 300 ppm for 2 days and after administration of unlabelled IQ (300 ppm) in the diet for approximately 6.5 wk for an additional 2 days. In the initial 48 hr following oral administration of 20 or 40 mg [2-14C]IQ/kg body weight, about 40-50% radioactivity was recovered in the urine, and about 30-38% radioactivity was recovered in the faeces. In the initial 72 hr following consumption of [2-14C]IQ (300 ppm) in the diet about 26% radioactivity was recovered in the urine and about 61% radioactivity was recovered in the faeces. Following cannulation of the bile ducts, rats administered a single dose of [2-14C]IQ (40 mg/kg body weight) by oral gavage excreted about 15% of the administered dose in the bile over a period of 2 days. Urine from rats given [2-14C]IQ contained three main polar metabolites that included a glucuronide, a sulphate ester and IQ sulphamate, and a number of less polar metabolites that included IQ, 2-acetylamino-3-methylimidazo[4,5-f]quinoline, 2-aminoimidazo[4,5-f]quinoline and 2-amino-3,6-dihydro-3-methyl-7H-imidazo[4,5-f]quinoline-7-one (7-OH-IQ). Administration of [2-14C]IQ by oral gavage or in the diet gave the same metabolites, but in different amounts. In the faeces of rats given [2-14C] by oral gavage, IQ-sulphamate was the major metabolite in the polar fraction. Non-polar metabolites similar to those found in the urine were also present, but in different amounts. A major, non-polar faecal metabolite, 7-OH-IQ was probably formed as a result of the activity of the intestinal bacterial flora. In rats given a single gavage dose of [2-14C]IQ, excretion of metabolites was higher in the urine and lower in the faeces compared with that in animals fed [2-14C]IQ in the diet. One polar metabolite present in the urine, IQ-sulphamate (39%), was found at considerably higher levels in rats dosed orally with IQ compared with those fed IQ (less than 6%). Thus, IQ is extensively metabolized to give a number of polar and non-polar metabolites, the amounts of which depend, in part, on the mode of dosing.     

Tissue-binding and toxicity of compounds structurally related to the herbicide dichlobenil in the mouse olfactory mucosa.

The herbicides dichlobenil (2,6-dichlorobenzonitrile), chlorthiamid (2,6-dichlorothiobenzamide) and their environmental degradation product 2,6-dichlorobenzamide are irreversibly bound and toxic to the olfactory mucosa following single injections in mice (Brandt et al., Toxicology and Applied Pharmacology 1990, 103, 491-501; Brittebo et al., Fundamental and Applied Toxicology 1991, 17, 92-102). In the present study, autoradiography showed an irreversible binding of radioactivity in the olfactory mucosa (preferentially in the Bowman's glands) in C57Bl/6 mice treated with the 14C-labelled analogues [14C]2,6-difluorobenzonitrile ([14C]DFBN) and [14C]2,6-difluorobenzamide ([14C]DFBA). Therefore the toxicity of DFBN, DFBA and of some structurally related compounds including benzonitrile (BN) and the herbicides bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and ioxynil (3,5-diiodo-4-hydroxybenzonitrile) in the mouse olfactory mucosa was examined. No histopathological changes in the olfactory mucosa or in the liver were observed following a single ip dose of any of these compounds [0.145 mmol/kg (all compounds); 0.58 mmol/kg (DFBN, DFBA and BN)]. Also in mice treated with the glutathione-depleting agent phorone, none of these compounds induced any histopathological changes in the olfactory mucosa. The covalent binding of [14C]DFBN in the olfactory mucosa was 16 times lower than an equimolar toxic dose of [14C]dichlobenil, suggesting a low rate of metabolic activation of DFBN in the olfactory mucosa or a low reactivity of the DFBN metabolites formed. The results of this study thus show that single doses of DFBN, DFBA, BN, IX and BX, compounds structurally related to the potent olfactory toxicant dichlobenil, do not elicit acute toxicity in the olfactory mucosa of mice.     

Nc100668, a new tracer for imaging of venous thromboembolism: disposition and metabolism in rats.

The 99mTc-complex of NC100668 [Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194] is being evaluated for nuclear medical imaging of venous thromboembolism. NC100668 is a 13-amino acid peptide with a Tc-binding chelator [NC100194; -NH-CH2-CH2-N(CH2-CH2-NH-C(CH3)2-C(CH3)=N-OH)2] linked to the C-terminal end. Following injection in rats of [Asn-U-14C]NC100668 (labeling of the N-terminal amino acid), approximately 70% of the radioactivity was recovered in urine within 3 days. Following injection of [Lys-U-14C]NC100668 (labeling close to the C-terminal amino acid), radioactivity was cleared more slowly, with only 8% recovered in urine and approximately 80% of the radioactivity present in the body after 3 days. The highest concentration of radioactivity in the body following injection of [Lys-U-14C]NC100668 was observed in the kidney inner cortex; this probably represents 14C-labeled Lys, which is reabsorbed in the kidney tubules and incorporated into protein metabolism. Metabolite profiling by high-performance liquid chromatography with radiochemical detection revealed that following injection of [Asn-U-14C]NC100668, there is a rapid appearance in blood of one peak containing radioactive metabolite(s) originating from the N-terminal part of the molecule. In urine samples, only this radioactive peak was observed with no intact NC100668 remaining; this very hydrophilic N-terminal metabolite was probably either the N-terminal amino acid or a very short peptide. Liquid chromatography-mass spectrometry analyses of rat urine samples obtained after injection of nonlabeled NC100668 confirmed the identity of two metabolites generated from the C-terminal end of the molecule; Gly-NC100194 was identified as the major of these metabolites and NC100194 as a minor metabolite present at approximately one-tenth the amount of Gly-NC100194. No other metabolites were identified.     

Toxicokinetics of monochloroacetic acid: a whole-body autoradiography study

Monochloroacetic acid (MCA) is a toxic chemical used as a herbicide and in the synthesis of various organic compounds. MCA has also been shown to be present in chlorinated drinking waters. In order to understand the mechanism of MCA toxicity, we studied the tissue distribution of [1-14C]MCA in rats, by whole-body autoradiographic technique. Male Sprague-Dawley rats were given a tracer dose of [1-14C]MCA [6.8 micrograms/100 g (40 mu Ci) body weight] by tail vein and euthanized at different time intervals (5 min, 1, 4, 12, 24 and 48 h). The animals were embedded in carboxymethyl cellulose and frozen immediately. Frozen animals were sectioned and processed using whole-body autoradiographic techniques. Analysis of developed sections showed that at 5 min, there was a rapid accumulation of 14C-activity in the kidney cortex and stomach walls. The radioactivity was rapidly removed from the circulation. There was high accumulation of 14C-activity in the myocardial tissues. The liver was also loaded with MCA and/or its metabolites. After 1 h following administration of [14C]MCA, radioactivity was extensively excreted into the small intestinal lumen. the accumulation of 14C-activity in the brain, thymus, salivary glands and tongue was prominent at 1 h. After 4 h the liver and other tissues started to eliminate most of the radioactivity. Contrary to other tissues, however, the central nervous system, thymus and pancreas started to accumulate the radioactivity at later time periods. These observations suggest the accumulation of MCA and/or its metabolites into hydrophilic tissues at earlier time periods and into lipophilic tissues at later times.     

Covalent binding of radioactivity from [14C]rofecoxib, but not [14C]celecoxib or [14C]CS-706, to the arterial elastin of rats.

Rofecoxib is a cyclooxygenase-2 (COX-2) inhibitor that has been withdrawn from the market because of an increased risk of cardiovascular (CV) events. With a special focus on the arteries, the distribution profiles of radioactivity in rats orally administered [14C]rofecoxib were investigated in comparison with two other COX-2 inhibitors, [14C]celecoxib and [14C]CS-706 (2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-1H-pyrrole), a novel selective COX-2 inhibitor. Whole-body autoradioluminography and quantitative determination of the tissue concentrations showed that considerable radioactivity is retained by and accumulated in the thoracic aorta of rats after oral administration of [14C]rofecoxib, but not [14C]celecoxib or [14C]CS-706. Acid, organic solvent, and proteolytic enzyme treatments of aorta retaining high levels of radioactivity from [14C]rofecoxib demonstrated that most of the radioactivity is covalently bound to elastin. In agreement with this result, the radioactivity was found to be highly localized on the elastic fibers in the aorta by microautoradiography. The retention of radioactivity on the elastic fibers was also observed in the aortic arch and the coronary artery. These findings indicate that [14C]rofecoxib and/or its metabolite(s) are covalently bound to elastin in the arteries. These data are consistent with the suggestion of modified arterial elasticity leading to an increased risk of CV events after long-term treatment with rofecoxib.     

Elimination and distribution of 2,2',4,5'-tetrachlorobiphenyl in laying hens

Laying hens were given a single oral dose of 2,2',4,5'-tetrachloro[14C]biphenyl ([14C]TCB). Within 11 days of administration, 54.8% of the original dose was excreted in the faeces. Examination of eggs laid within this period showed that 11.7% of the original dose was present in the yolks. The biological half-life of [14C]TCB in hens was 7 days. In hens killed on day 7, radioactivity could be detected in all the main tissues and organs. In both faeces and yolk, about 60% of the radioactivity could be attributed to metabolites.     

Tissue distribution and excretion of radioactively labelled compounds in the Wistar rat after administration of [N-methyl-14C]-erythromycin A

Tissue distribution and excretion of radioactively labelled compounds was studied in the Wistar rat after i.v. administration of [N-methyl-14C]-erythromycin A. Whole-body autoradiography and liquid scintillation counting was used to investigate the tissue localization of radioactivity in pregnant and non-pregnant rats. Tissue levels were maximal within 20 min, except for lachrymal glands, thymus and brain. Large amounts of radioactively labelled compounds, partly originating from active secretion, were present in the small intestine and caecum. Marked concentration of radioactively labelled compounds was also observed in the liver, spleen, lachrymal and salivary glands, lymph nodes, mammary glands, skin, bone marrow, and, to a lesser extent, in the lung, kidney and skeletal muscle. During six hours of experimental follow-up, plasma levels remained lower than corresponding tissue levels. At 1 h the radioactivity in fetuses was about three times lower than that in maternal blood. Within 48 h, more than 90% of the administered radioactivity was excreted. The amounts of radioactivity recovered in urine, faeces and expired air were about 19%, 48% and 24% respectively. After 48 h, 8% of the administered radioactivity was found in the carcass.     

Delta 9-tetrahydrocannabinol increases arachidonic acid levels in guinea pig cerebral cortex slices

Several studies have shown that the major psychoactive component in marihuana, (-)-(trans)-delta 9-tetrahydrocannabinol (THC), increases the level of unesterified arachidonic acid (AA) in non-neural cells in culture. Little is known, however, about the effects of THC on AA metabolism in the mammalian brain. In the present study, slices from guinea pig brain cortex were prelabeled with [14C]AA, and the effects of THC and other cannabinoids on the disposition of esterified and unesterified [14C]AA were measured. Incubation of prelabeled cortical slices with THC rapidly increased free [14C]AA levels in a dose-dependent and saturable manner. A maximal increase of over 4-fold was elicited by 32 microM THC, with the half-maximal response occurring at 8.0 microM. Comparison of the potencies of several other cannabinoids revealed that the inactive stereoisomer of THC [(+)-THC] was equipotent with the naturally occurring isomer in increasing unesterified [14C]AA levels. The relative rank-order of potencies in the cannabinoid series we examined were (-)-THC = (+)-THC greater than cannabinol greater than delta 8-THC greater than cannabidiol. We also measured cannabinoid-induced changes in the disposition of esterified [14C]AA in the neutral lipids and phospholipids of brain cortex slices. After incubation with 8 microM THC for 1 hr, the radioactivity in triacylglycerols was reduced by over one third. The loss of esterified [14C] AA from triacylglycerols accounted for less than 20% of the THC-induced rise in free [14C]AA; the remainder was accounted for by losses in the radioactivity contained in the phospholipid fraction, particularly from phosphatidylinositol. The loss in radioactivity from phosphatidylinositol alone accounted for over one half of the THC-induced rise in unesterified [14C]AA. The results of the present study indicate that in brain, as in extra-neural cells in culture, cannabinoids increase unesterified AA levels; however, the relative potencies of the cannabinoids we examined in increasing AA levels do not correlate well with their in vivo psychoactive potencies.