Absorption and elimination of a branched-chain alkylpolyethoxylate surfactant in rats.

Oral doses (100 mg/kg/day) of a 14C-labelled branched-chain alkylpolyethoxylate [( C5H11]2CH14CH2O[CH2CH2O]6H; abbreviated [14C]A12E6) were extensively absorbed from the gastrointestinal tract of rats. During a multiple dosing regime, a proportion of 14C equivalent to one daily dose was excreted each day. This 14C was excreted in urine and faeces in equal proportions; less than 1% of the dose was expired as 14CO2. Almost all the faecal 14C came from the bile and had undergone enterohepatic circulation. After cutaneous application of [14C]A12E6 to rats (8 mg, 333 micrograms/cm2) under occluded conditions, about 25% of the dose was absorbed, mainly during the first 12 h. After dosing by both routes, the A12E6 was biotransformed to several metabolites that were more polar than the parent compound. Less than 15% of the dose was excreted unchanged.

The effect of intravenously administered phosphocreatine on ATP and phosphocreatine concentrations in the cardiac muscle of the rat.

Following intravenous administration of 32P-phosphocreatine (50 mg/kg) or an equimolar mixture of creatine + 32P-phosphate (equivalent to 50 mg/kg phosphocreatine) to rats, and examination of an extract of cardiac muscle by HPLC, the proportion of radiolabelled adenosine triphosphate (ATP; up to 3%) was similar in each treatment group at 120 min after dosing. Mean concentrations of ATP in the cardiac muscle were increased significantly during this time (to 3.1 mumol/g) after intravenous administration of 32P-phosphocreatine compared with those in control rats (2.5 mumol/g) and in rats dosed with creatine + 32P-phosphate mixture (2.6 mumol/g). Phosphocreatine concentrations in cardiac muscle of phosphocreatine-treated rats were also increased (2.3 mumol/g) significantly after 120 min compared with controls (1.7 mumol/g), but were unchanged after 30 min. Mean concentrations of phosphocreatine in rats receiving a creatine + phosphate mixture were slightly reduced (1.3 and 1.5 mumol/g after 30 min or 120 min, respectively) compared with controls. The elevation of tissue ATP and phosphocreatine levels may be involved in the protective effect provided by exogenous phosphocreatine against anoxia in isolated cardiac muscle.

Effect of the triazolobenzodiazepine estazolam on hepatic drug-metabolizing enzyme activity in rats.

Oral doses of the sedative/hypnotic estazolam (500 mg kg-1 day-1) to rats for 21 days caused statistically significant increases in liver weight, ascorbate excretion, cytochrome P-450 concentrations, and in aniline hydroxylase, ethylmorphine N-demethylase and glutathione S-transferase activities, as did approximately equivalent doses of flurazepam hydrochloride. Histologically, the centrilobular hepatocytes were enlarged. Some of these parameters were also increased after doses of estazolam of 100 mg kg-1 day-1, but not after 5 mg kg-1 day-1, which is about 50-fold greater than a clinical dose. Estazolam was a much less potent enzyme inducer than phenobarbitone under the conditions of these studies.

The metabolism of the hypolipidaemic drug sultosilic acid in rat, dog and man.

1. Single oral doses of the hypolipidaemic drug [35S]sultosilic acid to rats (40 mg/kg), dogs (40 mg/kg) and man (7 mg/kg) were well absorbed. During three days, means of 59.2%, 58.8% and 61.8% in urine and 37.7%, 31.9% and 19.7% in faeces, were excreted by these species respectively. Most of the dose was excreted during the first 24 h. 2. Peak plasma levels of 35S were generally reached during 1-2 h after oral doses in rats (12 micrograms equiv./ml), dogs (45 micrograms equiv./ml) and two human subjects (15.2 and 10.3 micrograms equiv./ml). In humans, peak plasma levels of unchanged drug (at 1-1.5 h) were 10.5 and 6.3 micrograms/ml. Plasma concentrations of 35S increased almost proportionately to dose in rats following oral doses of 400 and 1200 mg/kg, although in dogs, concentrations were similar at these two dose levels but several times higher than at 40 mg/kg. 3. Tissue concn. of 35S were generally higher in rats than in dogs. Highest concn. occurred at 3 h in rats and 1 h in dogs. Apart from those in the liver and kidneys, tissue concn. were appreciably lower than the corresponding plasma levels. 4. The major radioactive component in dog urine was sultosilic acid. Rat and human urine contained sultosilic acid and also two more polar major metabolites. In male and female rat urine, the proportions of these excretory products differed and the proportions in male rat urine were similar to those in human urine. Sultosilic acid was also the only component detected in dog plasma, whereas rat and human plasma also contained the two urine metabolites. Dog bile contained a conjugate of sultosilic acid. 5. The two metabolites have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy as products resulting from oxidation of the methyl in the p-toluenesulphonyl group. The structures assigned are the corresponding carboxylic acid and the hydroxymethyl derivatives.

Metabolic fate of the beta-blocker 14C-bupranolol in humans, dogs, and rhesus monkeys.

An oral dose of 14C-bupranolol hydrochloride was well absorbed by humans (100 mg), dogs (1 mg/kg), and rhesus monkeys (1 mg/kg). These species excreted 87.8 and 3.5%, 81.1 and 13.6%, and 92.9 ad 5.0% of the 14C-dose in urine and feces, respectively, mainly in 12 or 24 hr. Mean plasma levels of 14C, which appeared to be almost entirely associated with a single metabolite, peaked at 1 hr in humans (1.6 micrograms-equiv./ml) and dogs (1.6 micrograms-/ml) and at 2 hr in monkeys (0.8 micrograms-equiv./ml). Concentrations initially declined with similar half-lives (about 1.5 hr) in all three species. Biliary excretion of 14C occurred in the animal species in which also peak plasma 14C levels exceeded those in most tissues. Unchanged bupranolol was not detected in plasma; the peak plasma and urinary 14C was mainly associated (greater than 90% in humans) with a metabolite produced by oxidation of the aromatic ring methyl group of bupranolol to a carboxyl group.

Factors affecting induction of lung aryl hydrocarbon hydroxylase in rats exposed to cigarette smoke.

Induction of lung aryl hydrocarbon hydroxylase (AHH) activity has been studied in rats following their exposure to different regimes of cigarette smoke produced from tobacco and the tobacco substitute NSM. The rate of induction of AHH was maximal during the first 3 days of exposure to tobacco smoke. The frequency of exposure to tobacco smoke was apparently more important in influencing induction of AHH than was the duration of the exposure. After cessation of exposure to smoke, AHH activity declined to control levels within about 3 days. Tobacco smoke was a more potent inducer of AHH than was smoke from NSM. Measurement of AHH may provide a useful means of assessing whether animals involved in toxicity studies of smoking materials inhale sufficient total particulate matter to provoke a biological response, such as induction of AHH.

The effect of caffeine on the absorption of 3H-dihydroergocryptine (DHEC) in the rat.

1. Following single oral doses of 3H-dihydroergocryptine (DHEC) to rats, most of the absorbed radioactivity was excreted in the bile, 18.5% +/- 3.2 SD after dosing with 3H-DHEC (0.1 mg/kg) and caffeine (1 mg/kg), and 15.1 +/- 4.6 SD after dosing with 3H-DHEC (0.1 mg/kg) alone. The exception data indicated that about 25% of a single oral dose of 3H-DHEC was absorbed. 2. During 7 h after the last of daily oral doses for 7 days, plasma concentrations of radioactivity were consistently significantly greater (P < 0.001 to < 0.01) in rats dosed with 3H-DHEC (0.1 mg/kg) and caffeine (1 mg/kg) than in those dosed with 3H-DHEC (0.1 mg/kg) alone. The extent of bioavailability of radioactivity was also signficantly greater during this time (P < 0.01) and during 24 h (P < 0.05) after the last of repeated oral doses of 3H-DHEC and caffeine than after 3H-DHEC alone.

Hepatic effects of xylidine isomers in rats.

The effect of repeated (4 weeks) oral administration of 2,4-, 2,5- or 2,6-xylidine (at dose levels of 400--500 mg/kg/day) on the morphology and microsomal drug metabolising enzyme activity of the liver was studied in rats. All 3 isomers caused hepatomegaly which was considered to be due to proliferation of the smooth endoplasmic reticulum. Decreases in glycogen content and glucose-6-phosphatase activity were demonstrated histochemically. Biochemical investigations showed increases in microsomal protein and cytochrome P-450 content in rats dosed with 2,4- or 2,5-xylidine and in glucuronyltransferase activity in rats given 2,4-, 2,5- or 2,6-xylidine. Aniline hydroxylase activity was increased in all treated rats except males dosed with 2,6-xylidine. The results of the study indicate that all isomes of xylidine can be inducers of microsomal drug-metabolising enzyme activity, that they may be metabolised by oxidation and that the xylidine molecule may be eliminated as a conjugate with glucuronic acid.

Renal and bone uptake of tartaric acid in rats: comparison of L(+) and DL-Forms.

Plasma concentrations of radioactivity declined biphasically with half-lives of about 15 and 58 h respectively in rats dosed with monosodium DL-[14C]tartrate for 7 days at a dose level of 2.73 g/kg/day. Uptake and retention of radioactivity occurred in blood cells, kidneys and bones where it was detected for at least 12 days after dosing. Renal retention (11202 +/- 4469 ppm at 6 h, n = 7) was probably due to precipitation of the poorly soluble calcium DL-tartrate in the tubules leading to increased kidney weight, nephrotoxicity and even death. The more soluble, naturally-occurring L(+)-[14C] tartrate was not retained in the kidneys (1287 +/- 118 ppm at 6 h, n = 8) when administered to rats under the same conditions, and the initial decline of plasma concentrations of radioactivity was more rapid (t 0.5 approx. 3 h). For this reason, monosodium L(+)-tartrate was non-toxic at 2.73 g/kg/day whereas monosodium DL-tartrate was toxic at this dosage.

Absorption and biotransformation of L(+)-tartaric acid in rats.

Oral or parenteral doses of monosodium 14C-L(+)-tartrate (400 mg/kg) are rapidly excreted by rats and a proportion completely metabolized to CO2. The oral dose was well-absorbed.

Concentrations of the vasodilator isosorbide dinitrate and its metabolites in the blood of human subjects.

An oral dose of 5 mg of 14C-isosorbide dinitrate was rapidly absorbed, biotransformed and excreted by human subjects. Peak whole blood concentrations of radioactivity were reached after 1.5 to 2 hours and declined relatively slowly. The radioactivity in whole blood mainly represented metabolites, isosorbide mononitrates. The peak concentrations found were 4.5, 11.7 and 34.3 ng/ml of isosorbide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate, respectively, in the blood of one subject and 5.9, 15 and 61.3 ng/ml, respectively, in the blood of another subject. However, concentrations of the metabolites declined relatively slowly during 6 h after the oral urine of the first day (ca. 78%). The results showed that isosorbide mononitrates were available to contribute to the pharmacological action.