Steady state kinetics of 14C-sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] metabolism in swine

Swine were dosed orally with 14C-sulfamethazine [4-amino-N-(4, 6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] for 3, 5, or 7 days (two 165-mg doses/day; 0.46 muCi/mg) and killed 8 hr after the last dose. The concentration of carbon-14 in the tissues increased by an average of 21% from day 3 to day 5 of dosing. However, there was no further increase from day 5 to day 7, indicating that a steady state level of carbon-14 in the tissues was attained by dosing on 5 consecutive days. Liver, kidney, skeletal muscle, blood, and adipose tissue from all animals were analyzed for 14C-labeled sulfamethazine, N4-acetylsulfamethazine, desaminosulfamethazine [N-(4, 6-dimethyl-2-pyrimidinyl)benzenesulfonamide], and the N4-glucose conjugate of sulfamethazine. The identity of these compounds (the hydrolysis product of N4-glucose conjugate) was confirmed by HLPC and gas-liquid chromatography/mass spectral analysis after methylation. The relative distribution of 14C-sulfamethazine and these metabolites varied somewhat among the tissues analyzed but did not vary within a tissue after different periods of dosing.     

Depletion kinetics of 14C-sulfamethazine [4-amino-N-(4, 6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] metabolism in swine

Swine weighing 60-70 kg were orally administered 14C-sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] at 12-hr intervals for 7 days (165 mg/dose; 0.126-5.04 mCi/mmol). The animals were sacrificed at 8 hr or 2, 5, or 10 days after the last dose was given and tissues were assayed for total 14C activity. The presence of 14C-labeled sulfamethazine, N4-acetylsulfamethazine, desaminosulfamethazine, and the N4-glucose conjugate of sulfamethazine in blood, liver, kidney, skeletal muscle, and adipose tissue was verified by HPLC and GC-MS analysis. Total 14C residue levels in all tissues examined had dropped to less than 0.1 ppm sulfamethazine equivalents by day 10 of the depletion period. The mean half-life (t1/2) for sulfamethazine, the N4-glucose conjugate of sulfamethazine, and N4-acetylsulfamethazine was estimated to be 0.8 day. In some tissues, the depletion of the N4-glucose conjugate of sulfamethazine and N4-acetylsulfamethazine had decreased significantly between days 5 and 10, resulting in an approximate doubling of the t1/2 for that period. In contrast, the half-life of desaminosulfamethazine varied from a mean of 0.96 day during the 8-hr-5-day depletion period to 3.7-9.1 days during the 5- 10-day depletion period. In most tissues, the t1/2 for the 14C-activity in the methanol-insoluble fraction increased by 3-5-fold between days 5 and 10 of the depletion period. No predictable relationship was observed between blood sulfamethazine or metabolite levels and total residue levels in the tissues.     

Metabolism of 1,3-di-(4-[N-(4,6-dimethyl-2-pyrimidinyl)sulphamoyl] phenyl)triazene (DDPSPT) in the rat

1. Six hours after rats were orally dosed with 1,3-di-(4-[N-(4,6-dimethyl-2-pyrimidinyl)sulphamoyl][U-14C]phenyl) triazene (14C-DDPSPT), approx. 81% of the 14C remained in the gastrointestinal tract (gut) and less than 3% was excreted in the urine. 2. Six hours after dosing, more than half of the 14C in the gut was present as DDPSPT. 14C-Labelled metabolites in the gut included 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)-benzenesulphonamide (Sulmet), N4-glucosyl-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (N4-gluc-Sulmet), 4-acetamido-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (N4-acetyl-Sulmet), and [N-4,6-dimethyl-2-pyrimidinyl) benzenesulphonamide] (desamino-Sulmet). 3. 14C-Labelled compounds in the blood, liver and skeletal muscle included DDPSPT, Sulmet, N4-gluc-Sulmet, N4-acetyl-Sulmet and desamino-Sulmet. 4. There was little or no reaction of DDPSPT with cysteine, bovine serum albumin, AMP, GMP, or calf thymus deoxyribonucleic acid in vitro (pH 3, 5, 7 or 8).     

The disposition of N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide in the rat

Rats given a single oral dose of N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide (14C-DAS) excreted 64.2% of the 14C in the urine and 22.4% in the feces within 96 hr. Compounds accounting for 86% of the 14C in the 0-24-hr urine were isolated by a variety of chromatographic techniques and identified by IR, NMR, and MS analysis. Approximately 4% of the 14C in the urine was the parent compound. The structures of 14C-metabolites in the urine indicated that 14C-DAS was metabolized by at least three pathways which included: 1) hydroxylation and glucuronic acid conjugation at the 4-position of the benzene ring; 2) hydroxylation, and sulfate ester and glucuronic acid conjugation at the 5-position on the heterocyclic ring; and 3) hydroxylation and glucuronic acid conjugation of one methyl group on the heterocyclic ring.     

Evidence for diazotization of 14C-sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] in swine. The effect of nitrite

Dietary nitrite greatly enhanced the conversion of orally administered 14C-sulfamethazine (4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide; 14C-sulmet) to 14C-desaminosulfamethazine [N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide; 14C-DA-sulmet] in swine. The disposition of 14C orally administered to swine as 14C-sulfamethazinediazonium tetrafluoroborate (4-[N-(4,6-dimethyl-2-pyrimidinyl)sulfonamido] [U-14C]diazonium tetrafluoroborate) was very similar to the disposition of 14C given to swine as 14C-sulmet in combination with nitrite. These results and other information discussed in the text provide evidence that 14C-sulmet, in the presence of nitrite under the acid conditions in the gastrointestinal tract, was diazotized and that this diazonium intermediate was converted to 14C-DA-sulmet and other unidentified 14C-labeled products.     

Characterization of products formed by the reaction of 14C-sulphamethazinediazonium tetrafluoroborate with natural products

1. When bovine serum albumin (BSA) was incubated with 4-[N-(4,6-dimethyl-2-pyrimidinyl)sulphonamido] [U-14C]benzenediazonium tetrafluoroborate (14C-SDTFB) in vitro approx. half of the 14C-activity was bound (14C-BSA). Cysteine, N-ethylmaleimide, p-chloromercuribenzoate and iodoacetamide inhibited the formation of 14C-BSA. 2. When SDTFB was reacted with cysteine four major products were formed. These were identified as 3-(4-[N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamido] diazothio)-2-aminopropionic acid (cys-SDAS), 3-(4-[4,6-dimethyl-2-pyrimidinyl) benzenesulphonamido]thio)-2-aminopropionic acid (cys-Sulmet), 4-hydroxy-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (hydroxy-Sulmet) and N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (desamino-Sulmet). Diazosulphides were also formed when SDTFB was incubated with thiophenol and glutathione. 3. The diazosulphides reacted with N,N-dimethylaniline (DMA) and 2-naphthol to yield diazo compounds in 22-29% yield; when 14C-BSA was reacted with DMA under the same conditions, a diazo compound was formed-but only in 2% yield. 4. Cys-SDAS when incubated overnight (approx. 16 h) in aqueous solutions (pH 3, 5 and 8) decomposed to yield desamino-Sulmet (30-39%), hydroxy-Sulmet (13-21%), and other unidentified soluble products (24-36%); when 14C-BSA was incubated under the same conditions only 3-4% of the 14C became dissociated from BSA and only a trace amount of desamino-Sulmet was formed. 5. When 14C-SDTFB was incubated with calf thymus DNA at pH3, some of the 14C became associated with the DNA (14C-DNA). However, most of the 14C became dissociated from 14C-DNA when the latter was incubated overnight in aqueous solutions; a minor dissociation product was identified as 14C-desamino-Sulmet.     

Disposition of a 14C-labeled bioerodible polyorthoester and its hydrolysis products, 4-hydroxybutyrate and cis,trans-1,4-bis(hydroxymethyl)cyclohexane, in rats

Disposition of the 14C-labeled bioerodible polymer poly(2,2-dioxy-cis,trans-1,4-cyclohexane dimethylene tetrahydrofuran) (ALZAMER C101ct) and its ultimate hydrolysis products, 4-hydroxybutyrate (4HB) and cis,trans-1,4-bis(hydroxymethyl)cyclohexane (CHDM), was assessed in vivo in rats 24 hr after sc administration of the 14C-labeled polymer or hydrolysis products. The hydrolysis products were rapidly metabolized and eliminated, whether administered directly or via in vivo erosion of the polymer. At 24 hr, fractional distribution of carbon-14 derived from 4HB was 65 to 75% in expired CO2, 5 to 10% in urine, 1 to 2% in feces, and 15 to 19% in tissues. For CHDM, distribution was 92 to 96% in urine, 2 to 3% in feces, and 0.3 to 3% in tissues. Hydrolysis products or metabolites were not sequestered in specific tissues. Pretreatment with unlabeled polymer for 28 days had little effect on the disposition of carbon-14. Minor differences in disposition between the polymer and its hydrolysis products are discussed.     

The fate of (14C)thiodipropionates in rats

Thiodipropionic acid and its esters are preservatives and stabilizers used in food and food packaging. The oral fate in rats, hitherto unknown, of thiodipropionic acid (TDPA), didodecyl thiodipropionate (DDTDP), and of a polyester of thiodipropionic acid with cyclohexane-1,4-dimethanol partially terminated with stearyl alcohol, POLY-TDPS-2000 (TDPS), was elucidated in evaluating TDPS as a polymer stabilizer.Single doses of [1-¹⁴C]TDPA were rapidly eliminated, 87–95% of 241–650 mg/kg doses being recovered in 4 days in urine (78–88%), and feces (0.1–0.9%) and as ¹⁴CO₂ (3–8%). Radioactivity in tissues and organs was less than 1.5 × background. A 3-mg/kg dose of [1-¹⁴C]TDPA was handled similarly. Urinary radioactivity at the higher dose was due almost entirely to unchanged TDPA, while the lower dose apparently gave an acid-labile conjugate of TDPA.Single oral doses of [1-¹⁴C]DDTDP (107 and 208 mg/kg) were rapidly eliminated, mostly in the urine (85–88%), with less in feces (1.8–3.5%) and as ¹⁴CO₂ (3–4%, by day 4); 1-day dietary feeding of 166 mg/kg gave similar results. Tissue and organ levels of radioactivity at sacrifice were close to background, with the exception of fat levels, which were elevated 34 days after dosing. Urinary radioactivity was mostly unchanged TDPA or an acid-labile conjugate.Five-hour feeding in the diet of each of 3 rats of 4.7–5.6 mg/kg of ¹⁴C-labeled TDPS prepared from [1-¹⁴C]TDPA, was almost entirely eliminated by 4 days in urine (95%) and feces (0.7%) and as ¹⁴CO₂ (approx. 6%). At sacrifice 4 days after dosing, tissue and organ radioactivity was slightly above background, and at 34 days essentially normal. Almost two-thirds of the urine radioactivity was due to [1-¹⁴C]TDPA or a conjugate.TDPA is in many respects similar to a typical dicarboxylic acid after oral intake in being rapidly absorbed and eliminated in the urine largely unchanged. Simple esters and polyesters of TDPA appear to be readily hydrolyzed in the organism to the parent acid, which is then eliminated similarly to TDPA given orally.     

Disposition of 14C-alpha-cyclodextrin in germ-free and conventional rats

The absorption, disposition, metabolism, and excretion of uniformly (14)C-labeled alpha-cyclodextrin ((14)C-alpha-CD) was examined in four separate experiments with Wistar rats. In Experiment 1, (14)C-alpha-CD (25 microCi, 50 mg/kg bw) was administered intravenously to four male and four female conventional rats. In Experiment 2, (14)C-alpha-CD (25 microCi, 200 mg/kg bw) was given by gavage to four male and four female germ-free rats. In Experiments 3 and 4, (14)C-alpha-CD was given to groups of four male and four female conventional rats by gavage at different dose levels (100 microCi, 200 mg/kg bw; 25 microCi, 200 and 100 mg/kg bw). In all experiments, (14)C was measured in respiratory CO(2), urine, and feces over periods of 24-48 h, and in the contents of the gastrointestinal tract, blood, main organs, and residual carcass at termination of the experiments. The chemical identity of the (14)C-labeled compounds was examined by HPLC in blood (Experiment 1), urine (Experiments 1-4), feces (Experiments 2-4), and samples of intestinal contents (Experiments 2 and 4). Recovered (14)C was expressed as percentage of the administered dose. Experiment 1 showed that intravenously administered alpha-CD is excreted rapidly with urine. During the first 2h after dosing, plasma (14)C levels decreased rapidly (t(1/2), 26 and 21 min in male and female rats, respectively). About 13% of the administered (14)C dose (range 4.6-30.6) was detected in the feces, respiratory CO(2), organs, and carcass at the end of the experiment, i.e., 24 h after dosing. The presence of about 1.9% in the intestinal contents and feces suggests that a certain fraction of systemic alpha-CD is eliminated with the bile or saliva. Conclusive evidence, either positive or negative, for a hydrolysis and further metabolism of a small fraction of the administered alpha-CD by the enzymes of the mammalian body could not be gained from this experiment. Upon oral administration of (14)C-alpha-CD to germ-free rats (Experiment 2), about 1.3% of the label expired as CO(2) within 24 h. In the urine collected from 0 to 8 h after dosing, (14)C-alpha-CD was the only radiolabeled compound detected. The amounts of alpha-CD detected in the urine suggest that on average about 1% of an oral dose is absorbed in rats during small-intestinal passage. In conventional rats (Experiments 3 and 4), a delayed appearance of respiratory (14)CO(2) was observed which is attributed to the non-digestibility of alpha-CD and its subsequent microbial fermentation in the cecum and colon. In the urine collected at 4 h after dosing, a small amount of unchanged (14)C-alpha-CD was detected which confirms that about 1% of the ingested alpha-CD is absorbed intact and is excreted via the kidneys. No (14)C-alpha-CD was found in the feces. It is concluded from the data that ingested (14)C-alpha-CD is not digested in the small intestine of rats but is fermented completely by the intestinal microbiota to absorbable short-chain fatty acids. Therefore, the metabolism of alpha-CD resembles closely that of resistant starch or other fermentable dietary fibers.     

The effect of dietary nitrite and nitrate on the metabolism of sulphamethazine in the rat

Rats given 100 p.p.m. of 14C-sulphamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulphonamide] in the diet excreted less 14C-activity in the urine as the amount of nitrite (0 to 1000 p.p.m.), but not nitrate (3730 p.p.m.), in the diet was increased. As the level of nitrite, but not nitrate, was increased, there was a concomitant increase in the amount of 14C-desaminosulphamethazine (4-[(N-4,6-dimethyl-2-pyrimidinyl)benzene-[U-14C]-sulphonamide in the blood, liver, skeletal muscle and gastrointestinal tract. As the level of nitrite, but not nitrate, supplementation was increased, the amount of methanol-insoluble 14C-activity in the gastrointestinal tract increased but the amount of insoluble 14C-activity in the blood, skeletal muscle and liver was not changed.     

Studies on the metabolic fate of [14C]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the mouse

Studies on the Metabolic Fate of [14C]2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in the Mouse. KOSHAKJI, R. P., HARBISON, R. D., and BUSH, M. T. (1984). Toxicol. Appl. Pharmacol. 73, 69-77. After a single po dose (135 micrograms/kg; 62 microCi/kg) of 14C-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in male ICR/Ha Swiss mice, 67 to 76% of the administered dose was eliminated via the feces and 1 to 2% in the urine during the first 24 hr following treatment. It seems likely that most of this material was simply not absorbed. Much of the remaining chemical was then excreted slowly in the urine (2%) and feces (7%) during the next 10 days, partly as the unchanged compound and partly as metabolites. One of the metabolites (Fraction II) appears to be a single polar, acidic metabolite characterized in urine (0.4 +/- 0.1%) and feces (2.2 +/- 0.2%), and is also likely excreted as a glucuronide conjugate. The rest of the radioactivity was in the form of unchanged TCDD in the animal body (17 +/- 2%). Steady rates of decline in the concentrations of the 14C as well as of the unchanged TCDD were reached in the feces and urine after the fifth day following the administration of the chemical. Based on this steady rate, the half-life of the radioactivity in the body was approximately 20 days. Urine, feces, and whole body were analyzed by solvent extraction, 14C counting, thin-layer chromatography, and countercurrent distribution.     

Lactose conjugation of sulphonamide drugs in the lactating dairy cow.

1. 14C-Sulphamethazine (4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene-[U-14C]-sulphonamide; 220 mg/kg of body weight) was given orally or i.v. to lactating dairy cows. Milk collected from 0-48 h after dosing accounted for 2.0% (oral dose) and 1.1% (i.v. dose) of the total 14C-activity administered. 2. Sulphamethazine accounted for 70-79% (oral dose) and 54-75% (i.v. dose) of the total 14C in milk samples collected from 0-48 h after dosing. N4-acetylsulphamethazine accounted for 1-2% (oral dose) and 1-4% (i.v. dose) of the 14C in milk. 3. The major 14C-labelled metabolite in the milk was isolated and identified as the N4-lactose conjugate of sulphamethazine, a unique type of metabolite not previously reported. This metabolite accounted for 10-14% (oral dose) and 9-20% (i.v. dose) of the 14C-activity in the milk collected from 0-48 h after dosing with 14C-sulphamethazine. 4. N4-lactose conjugates of sulphapyridine, sulphamerazine, sulphathiazole, sulphadimethoxine and sulphaquinoxaline were present in the milk from cows orally dosed with these five sulphonamide drugs.     

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 fate of inhaled octane and the nephrotoxicant, isooctane, in rats

To determine if inhaled nephrotoxic branched and nonnephrotoxic straight chain alkanes differ substantially in their biological fate, male F344 rats were exposed to 14C-labeled isooctane and octane vapors at approximately 1 and 350 ppm by the nose-only mode for 2 hr. Radioactivity in exhalant, urine, and feces was determined for 70 hr post exposure, after which residual radioactivity in the rat carcasses was determined. Absorbed [14C]isooctane equivalents were eliminated almost exclusively via the kidneys, while absorbed [14C]octane equivalents were excreted about equally via the kidneys and as 14CO2. Kidney excretion of isooctane-introduced 14C was protracted over the entire 70 hr postexposure observation period whereas for octane-introduced 14C, kidney excretion was essentially complete after 10-20 hr. About 5% of the [14C]octane equivalents inhaled at 1 ppm remained in the carcass 70 hr after inhalation exposure. Two percent of the [14C]octane equivalents inhaled at 350 ppm and 1-2% of the [14C]isooctane equivalents inhaled at either 1 or 350 ppm remained in the carcass 70 hr after inhalation exposure. The different patterns of excretion of metabolites of isooctane compared to octane may be a factor affecting the differences in nephrotoxicity between these two compounds.     

Disposition of14C-Erythritol in Germfree and Conventional Rats

The metabolism and disposition of U-¹⁴C-erythritol was examined in four groups of three male and three female, nonfasted rats each. The rats of groups A and D were germfree; the rats of groups B and C were kept under conventional conditions. The rats of group B received an erythritol-supplemented diet for 3 weeks prior to the experiment (adapted rats). The rats of groups A, C, and D were kept on an ordinary diet which was sterile for groups A and D (not adapted rats). On the day of the experiment, each rat was dosed with U-¹⁴C-erythritol by gavage (5 μCi/kg body wt; sp act 50 μCi/g erythritol). The radiochemical purity of the erythritol was 96.43% for groups A–C. Group D, which was attached to the study after evaluation of the results of groups A–C, received a more purified erythritol with a radiochemical purity of 99.46% because the data of group A pointed to a possible interference by a¹⁴C-labeled impurity in the commercial¹⁴C-erythritol. After dosing, respiratory CO₂and urine were collected from each rat at regular intervals for 24 hr. At termination, feces were also collected. The animals were killed and intestinal contents, organs, tissues, and the remaining carcass processed for determination of¹⁴C.¹⁴C was excreted rapidly in the urine of all groups (range of groups A–D: 47.3–60.6% of the administered dose within the first 4 hr). Total 24-hr urinary excretion varied between 67.0% (group B) and 81.4% (group D). HPLC analysis of the urine showed that more than 96% of the eluted radiolabel represented erythritol. Conventional, adapted rats expired more¹⁴CO₂than conventional, unadapted rats [10.9% (B) vs 6.7% (C)]. Germfree rats expired much less¹⁴CO₂[0.8% (A) and 0.3% (D)]. In germfree rats,¹⁴CO₂expiration started shortly after dosing, reaching half of the 24-hr excretion after about 2.5 hr. In conventional rats¹⁴CO₂expiration started with a delay of about 2 hr reaching half the 24-hr excretion after 4–6 hr. The excretion of¹⁴C with feces was similar in all groups (8.3% on average of all rats). Slightly more¹⁴C was retained in the intestinal contents of germfree than conventional rats (1.9 vs 0.5%). The body retention was higher in conventional than in germfree rats (3.4 vs 2.0%). In group D, body retention was lowest (1.6%). The total recovery of¹⁴C was similar in all groups (95.6%, average of all rats). It is concluded that ingested erythritol is efficiently absorbed mainly from the small intestine, is not metabolized to a relevant extent in the body, and is excreted unchanged in the urine. The fraction of erythritol not absorbed is fermented by the gut microflora to intermediate products which are largely absorbed and metabolized. The data support a proposed physiological energy value for erythritol of about 0.5 kcal/g.     

The disposition and metabolism of [14C]fluconazole in humans.

The disposition and metabolism of 14C-labeled fluconazole (100 microCi) was determined in three healthy male subjects after administration of a single oral capsule containing 50 mg of drug. Blood samples, total voided urine, and feces were collected at intervals after dosing for up to 12 days post-dose. Pharmacokinetic analysis of fluconazole concentrations showed a mean plasma half-life of 24.5 hr. Mean apparent plasma clearance and apparent volume of distribution were 0.23 ml/min/kg and 0.5 liter/kg, respectively. There was no evidence of any significant concentrations of metabolites circulating either in plasma or blood cells. Mean total radioactivity excreted in urine and feces represented 91.0 and 2.3%, respectively, of the administered dose. Mean excretion of unchanged drug in urine represented 80% of the administered dose; thus, only 11% was excreted in urine as metabolites. Only two metabolites were present in detectable quantities, a glucuronide conjugate of unchanged fluconazole and a fluconazole N-oxide, which accounted for 6.5 and 2.0% of urinary radioactivity, respectively. No metabolic cleavage products of fluconazole were detected.     

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.     

The disposition and metabolism of a hypnotic benzodiazepine, quazepam, in the hamster and mouse

The disposition of 14C-quazepam (7-chloro-(2,2,2-trifluoroethyl) [5-14C]-5-o-fluorophenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-thione), a new benzodiazepine hypnotic, was studied in hamsters and mice after iv and po dosing. In both species, quazepam was rapidly absorbed, as indicated by the plasma Cmax being reached within 1 hr of an oral dose (5 mg/kg). Also, radioactivity is essentially completely absorbed in both species, since the percentage of dose excreted in the urine was not dependent on the route of drug administration. Radioactivity was widely distributed in the tissues of both species; however, it was concentrated (relative to plasma) only in the liver and kidneys. In hamsters, 66-77% of the radioactivity was excreted within 48 hr, and 97% within 7 days of dosing (57% found in urine and 40% in feces after iv; 54% in urine and 43% in feces after po dosing). In mice, 86-88% of the radioactivity was excreted within 24 hr, and 98% within 4 days of dosing (43% in urine and 56% in feces after iv, 37% in urine and 61% in feces after po dosing). In both species, plasma levels of quazepam, measured by GLC, accounted for a very small percentage of plasma radioactivity and the elimination half-life was short (2.4 hr in hamster and 1.2 hr in mice), indicating extensive first pass metabolism for this drug. TLC analysis of plasma and urine extracts from both species showed biotransformation of quazepam involved substitution of oxygen for sulfur, followed by: (a) N-dealkylation, 3-hydroxylation, and conjugation or (b) 3-hydroxylation and conjugation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives.

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, (1)H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.     

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, ¹H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.