Pharmacokinetics and disposition of triptonide in rats

Triptonide, isolated from Tripterygium wilfordii Hook., was found to show significant antiinflammatory, immunosuppression and antitumor activities. A RP-HPLC method was applied to determine the plasma concentration of triptonide at different times in rats. Concentration-time curves after i.v., 0.7, 1.4 and 2.8 mg.kg-1 of triptonide were fitted to a two-compartment open model with T1/2 alpha of 0.167-0.195 h and T1/2 beta of 4.95-6.49 h. The area under curves (AUCs) were linearly related to the dosages (gamma = 0.9894). Systematic clearances (CLs) were independent of dosages. Mean residence time (MRT) of the three doses was 3.26-5.14 h by noncompartmental (the statistical moment method) analyses. The tissue distribution of triptonide in rats appeared to be wide throughout the body. The triptonide levels were high in the lung and liver, moderate in the heart, kidney, spleen and muscle and low in the testis, intestine and brain. Data of the urine and bile excretion indicated that only a small percent of unchanged triptonide was excreted. Plasma protein binding of triptonide rate was about 75%.     

Metabolic disposition of chlorambucil in rats

1. The metabolic dispositionof chlorambucil, 4-p-(di-2-chloroethyl)aminophenylbutyric acid, was studied in the rat. 2. After oral administration of [14C]chlorambucil to rats, plasma, liver, and kidney showed the highest concentration of 14C. After intravenous administration, plasma and kidney were heavily labelled. Although plasma contained as much as 10% of the administered dose in the first few hours after administration, the level decreased to 1% by 24 h. Elimination of radioactivity was mainly through the kidney. 3. Ten metabolites were isolated and characterized by mass spectrometry. Most metabolites had undergone oxidation on the butyric acid side-chain to form phenylacetic acid and benzoic acid derivatives. Spontaneous degradation products of [14C]chlorambucil were analysed and compared with the metabolites.     

Stereoselective disposition of hydroxychloroquine and its metabolite in rats

Racemic hydroxychloroquine-sulfate (HCQ-sulfate) was administered to rats orally. Groups of 9 male and 9 female rats received doses of 0, 8, 16, or 24 mg/kg/day for 6 weeks, followed by a reduction of the higher doses to 8 mg/kg/day for the duration of the study. Whole blood samples were collected at 0, 3, 6, 8, and 10 weeks, and eleven tissues were harvested after the tenth week. The concentrations and enantiomer ratios of the parent drug and three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), were determined. The highest concentration of HCQ was found in the intestinal smooth muscle, and the lowest in the brain and adipose tissue. The highest concentrations of the metabolites were found in the liver, adrenals, and lung tissue. The metabolism of HCQ in the rats was found to be stereoselective with R/S > 1 for the drug and < 1 for the metabolites. Gender-specific differences in the proportions of the drug and its metabolites and their enantiomers in blood and tissue were found. Varying dosages appeared to have only a temporary influence on blood concentrations and not to effect the enantiomer ratios in blood. Only a limited number of tissues exhibited significant differences between dose groups. There were no observed differences in enantiomer ratios among the blood collection times.     

Stereoselective disposition of tiaprofenic acid enantiomers in rats

The development of cysts of Blastocystis hominis isolated from human feces by the Ficoll-Paque concentration method and cultured in Jones' medium containing 10% horse serum is described. The morphological changes were studied by light and transmission electron microscopy at different intervals for up to 48 h. The cysts developed into a large number of vacuolar forms within 24 h, and binary fission was the only mode of reproduction observed.     

Percutaneous absorption and disposition studies of methotrexate in rabbits and rats

The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5.9 +/- 2.8 ng mL-1) which appeared at approximately 2 h postdose and declined with the elimination half-life of 4.48 +/- 1.74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49.0 +/- 19.8 micrograms g-1), muscle (12.7 +/- 3.3 ng g-1), and SF (19.2 +/- 10.1 ng g-1) underneath the dosed stifle joint were significantly higher (p < 0.05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (approximately 59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1.8 and 2.6 times higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26.3 +/- 8.3 and 48.8 +/- 5.2 mg, respectively. A significant enhancer effect of N,N-diethyl-n-toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed (p < 0.05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a linear calibration curve (r > 0.999) over the range of 2-50 ng mL-1. quantitation limit of 0.5 ng mL-1, and mean recovery of approximately 87% was used for the quantitation of MTX in the tissue and fluid samples.     

Tenoxicam: acute dose-dependent disposition studies in rats

Single intravenous bolus doses of tenoxicam of 2.5, 5, and 10 mg/kg were administered to male Wistar rats to determine the effects of dose on tenoxicam pharmacokinetics. Predicted apparent volume of distribution at steady state (Vdss) and total plasma clearance (CL) were, respectively, 42 and 45% higher in the animals given 10-mg/kg dose than the animals given 2.5- and 5-mg/kg doses. Binding of tenoxicam to plasma proteins showed saturability, with a 33% higher unbound fraction of tenoxicam in plasma when total drug concentration in plasma was 36 mg/L (high dose group) in comparison with animals given the low doses (12 and 20 mg/L). The blood-to-plasma concentration ratio of tenoxicam was concentration independent and therefore did not account for the observed dose-dependent changes in Vdss and CL.     

Metabolism of rosmarinic acid in rats

The urine of rats administered rosmarinic acid (7) orally contained seven metabolites, which were identified as trans-caffeic acid 4-O-sulfate (1), trans-m-coumaric acid 3-O-sulfate (2), trans-ferulic acid 4-O-sulfate (3), trans-caffeic acid (4), m-hydroxyphenylpropionic acid (5), trans-m-coumaric acid (6), and unchanged rosmarinic acid (7) by spectroscopic and chemical data. The total cumulative amount of 1-7 excreted in the urine 48 h after the oral administration of rosmarinic acid was approximately 31.8% of the dose administered. On the other hand, the metabolites attributed to rosmarinic acid could not be found in the bile. Orally administered rosmarinic acid may thus be concluded to be excreted in the urine rather than in the bile, with cleavage of ester bonds, selective para-dehydroxylation, methylation, and sulfate-conjugation. Metabolites 2, 3, 5, and 6 were also detected in the plasma.     

Effects of probenecid and cimetidine on renal disposition of ofloxacin in rats

The renal handling of ofloxacin in rats which were given ofloxacin either alone or in combination with probenecid or cimetidine was studied. In the presence of cimetidine or probenecid, ofloxacin's total and renal clearances were reduced and its half-life was prolonged. This suggests that ofloxacin is secreted by both the anionic and cationic transport systems.     

Metabolism and disposition of 14C-granisetron in rat, dog and man after intravenous and oral dosing

1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man. 4. In rat and dog, 35-41% of the dose was excreted in urine and 52-62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.     

Metabolism of three cyclic nitrosamines in Sprague-Dawley rats

The metabolism of three cyclic nitrosamines has been studied in Sprague-Dawley rats. The compounds were nitrosopyrrolidine, nitrosohexamethyleneimine, and nitrosohepatamethyleneimine and were labeled at the alpha carbon with 14C. At low doses (2 to 4 mg/animal) the compounds were metabolized to 14CO2 to the extent of 77, 43, and 27%, respectively, after 24 hr. At doses closer to the 50% lethal dose of the compounds (70 to 160 mg/animal) the metabolism values were only 14, 4, and 8%, respectively, after 24 hr. The significance of these results is discussed.     

Metabolism of N-ethyl-3-piperidyl benzilate in rats

The metabolic fate of N-ethyl-3-piperidyl benzilate (I) and its potential metabolites 3-piperidyl benzilate (II), N-ethyl-3-hydroxypiperidine (III), and 3-hydroxypiperidine (IV) was studied. Incubation of I with rat liver homogenates resulted in the formation of II and III. Only a trace of unchanged drug appeared in urine after intraperitoneal injection of I. Approximately 9% of the injected dose of I was excreted in urine as III and 2% in the form of metabolites that produced III after acid hydrolysis. After intraperitoneal injection of II in rats, 18% of the dose was excreted in urine as IV. Approximately 26% of the injected dose of III was present in urine as the unchanged drug, and 63% of the dose was excreted in the urine in the form of conjugates that produced III on acid hydrolysis. Urine of rats injected with IV contained approximately 50% of the injected dose as the unchanged drug and 50% of the dose in the form of a conjugate that produced IV on acid hydrolysis. The identity of the metabolites in extracts from urine was established by GLC-mass spectrometry. It is concluded that hydrolysis was one metabolic pathway for I and II. The major routes of elimination of these compounds are not yet known and may include excretion in feces or metabolic transformations resulting in the degradation of the piperidine ring.     

Metabolism of carvedilol in dogs, rats, and mice

The excretion and biotransformation of carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-p ropanol], a new, multiple-action, neurohormonal antagonist that exhibits the combined pharmacological activities of beta-adrenoreceptor antagonism, vasodilation, and antioxidation, were investigated in dogs, rats, and mice. Carvedilol was absorbed well, and biliary secretion was predominant in each species. Carvedilol was metabolized extensively in each species, and elimination of unchanged compound was minor in bile duct-catheterized rats and dogs. In dogs, glucuronidation of the parent compound and hydroxylation of the carbazolyl ring, with subsequent glucuronidation, were the major metabolic pathways. Rats showed the simplest metabolite profile; the primary metabolites were formed by hydroxylation of the carbazolyl ring, with subsequent glucuronidation. Mice displayed the most complicated metabolite profile; glucuronidation of the parent compound and hydroxylation of either the carbazolyl or phenyl ring, with subsequent glucuronidation, were the major metabolic routes. O-Dealkylation was a minor pathway in all species examined.     

Comparison of the T cell-independent antibody response of mice and rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

In a prospective population-based cohort study, we assessed whether bone mineral density (BMD) measurements of perimenopausal women and other risk factors for osteoporosis are predictive of subsequent fracture. Women aged 47-51 years chosen randomly from a population register who underwent a bone density measurement 2 years previously were followed up by questionnaire to assess the 2-year incidence of any self-reported fractures. We found that 44 women, out of 1857 who completed the questionnaire, sustained at least one fracture within a 2-year follow-up period. After adjustment for covariates, the odds ratio of sustaining a fracture was 1.6 (95% confidence interval [CI] 1.16-2.34) for every standard deviation reduction in BMD at the spine, for women with a prior history of fracture the odds ratio of a subsequent fracture was approximately 2 (95% CI 1.31-3.03), a family history of hip fracture (maternal grandmother) carried an odds ratio of 3.7 (95% CI 1.55-8.85), while being postmenopausal or having a hysterectomy resulted in an odds ratio of 1.98 (1.02-3.56). This study has shown that BMD measurements at the hip and spine and other risk factors predict any nonhip and nonspine perimenopausal fractures. Further follow-up is required to assess the predictive performance of BMD measurements and other risk factors for hip and spine fractures.     

Comparative metabolism and disposition of gemfibrozil in male and female Sprague-Dawley rats and Syrian golden hamsters

Antibodies (Abs) can contribute to the cure of a viral infection, in principle, in two ways by: (1) binding to infected cells and thereby reducing the production of progeny virus [here termed cell-targeting (CT) activity] and (2) reacting with released progeny virus and thereby inhibiting the spread of the infection [termed virus neutralizing (VN) activity]. We have previously shown that a pulmonary influenza virus infection in severe combined immunodeficient mice could be cured by treatment of these mice with hemagglutinin (HA)-specific monoclonal Abs (mAbs) that mediated both of the above activities. Although the therapeutic activity of these mAbs correlated with their VN activity, it remained unclear how much their CT activity contributed to the Ab-mediated recovery process. To clarify this point, we tested the therapeutic efficacy of two mAbs of IgG2a isotype that mediated CT but no VN activity: one specific for the viral neuraminidase and the other for matrix protein 2. Both mAbs reduced pulmonary virus titers by 100- to 1000-fold but they failed to clear the infection, even when administered in combination and at therapeutically saturating concentrations. The results suggest that CT activity contributes significantly also to the therapeutic activity of HA-specific mAbs and further support the notion that VN-activity is required for Ab-mediated virus clearance.     

Metabolism of 109Cd in rats fed normal and low-calcium diets

Growing male rats were fed purified diets that contained either 0.6% or 0.1% calcium to investigate the relationship of calcium intake to the uptake, tissue distribution, and excretion of 109Cd. An equal number of rats were fed either the 0.6 or 0.1% calcium diets for 4 wk before they were used for experiments. In the first experiment 11 rats from each dietary group were administered 5 muCi 109Cd by stomach tube and were then maintained in metabolism cages for 72 hr. Animals fed the low-calcium diet took up more 109Cd, as significantly higher levels of radioactivity were found in the intestinal mucosa, serum, lungs, liver, kidneys, and urine and a significantly lower level was found in the feces. Higher levels of 109Cd, associated with low-molecular-weight proteins that may be related to the absorption process, were found in the intestinal mucosa of the low-calcium group. In the second experiment 10 rats from each dietary group were administered 5 muCi 109Cd by subcutaneous injection and then maintained in a metabolism cage for 72 hr. No significant differences were found in the distribution or excretion of 109Cd except for the lungs where radioactivity was greater in the low-calcium group. The results of the study indicate that the enhanced cadmium toxicity observed in calcium-deficient animals exposed to the heavy metal is the result of an increased uptake from the small intestine.     

Percutaneous absorption and disposition of [14C]chlordecone in young and adult female rats

The objective of this study was to evaluate the effect of age and dosage on percutaneous absorption and disposition of [14C]chlordecone (Kepone) and to describe results using a physiological based pharmacokinetic (PBPK) model. Female Fischer 344 rats 33 and 82 days old were used as the young and adult animal models, respectively, and were studied over a 10-fold dose range. [14C]Chlordecone (0.286 micromol/cm2) was applied to dorsal skin (2. 3% BSA) and radioactivity was quantified in selected tissues and excreta up to 120 h. Absorption and disposition were also determined at three dose levels up to 2.68 micromol/cm2; fraction absorbed decreased as dose increased. In vitro percutaneous absorption was measured by static and flow-through methods; these yielded similar penetration rates, which were lower than those obtained in vivo. In vivo percutaneous absorption over 120 h was 14.4+/-0.99 and 14.2+/-1. 5% dose in young and adults, respectively. Organ and tissue content increased over time (carcass>liver>kidney), indicating prolonged absorption. Statistical differences between young and old were found for liver, skin, and urine, but not for absorption. Excretion occurred primarily in feces, but also in urine. A biophysically based percutaneous model was fitted to both young and adult in vivo absorption data. This was embedded in a whole body PBPK model which, upon optimization with SAAM II, estimated apparent tissue partition coefficients, urinary and fecal excretion rates, and parameters characterizing hepatic nonlinear uptake of bound chlordecone. The model reasonably predicted tissue chlordecone content at higher doses, when decreased absorption was accounted for.