Disposition of flavodilol in laboratory animals

The disposition of flavodilol, a novel antihypertensive agent, was investigated in rats, rabbits, and dogs following iv or oral administration of 14C-flavodilol or unlabeled drug. Peak, plasma levels occurred within 6 hours of an oral dose in all three species. Following an iv dose, plasma elimination half-lives of flavodilol in rats, rabbits, and dogs were 3.0, 3.0, and 4.0 hr, respectively. Total body clearances were 0.71 liter/hr/kg for the rat, 1.89 liters/hr/kg for the rabbit, and 3.07 liters/hr/kg for the dog. Renal clearances were a small fraction of total clearance at 0.042, and 0.114 liter/hr/kg for the rat and dog, respectively, suggesting extensive nonrenal clearance. The volumes of distribution of 3.04 for the rat, 8.10 for rabbit, and 18.13 liters/kg for dog are large, suggesting significant extravascular distribution of flavodilol. Following 10 and 50 mg/kg po doses of 14C-flavodilol in rats, recovery of total radioactivity after 79 hr was 100.7% and 88.4% of the dose, respectively, most of which was recovered in the feces (77.5% and 66.6%, respectively). Tissue distribution studies of 14C in rats at 1.5, 5, 24, and 48 hr after a single po dose of 10 mg/kg 14C-flavodilol showed that the majority of the radioactivity was in the gastrointestinal tract and organs of elimination at all time points. Less than 1% of the dose remained in the body at 48 hr. 14C-Flavodilol was administered to rats iv at 1 mg/kg and orally at 10 mg/kg to assess comparative (label vs. nonlabel) absorption and distribution characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of flobufen and its main active metabolite in the rat

Pharmacokinetic study of the anti-inflammatory [3H] flobufen (I) and its active metabolite (II) has been carried out in rats given po and iv doses of 2, 10, and 50 mg/kg I and equimolar doses of II. Various pharmacokinetic parameters of I and II [dose normalized AUC; mean residence time (MRT); systemic blood clearance; steady state volume of distribution, (Vss)] are dose-independent. I is completely absorbed from the gastrointestinal tract and is rapidly (MRT = 7.2 hr) converted to II, which is slowly (MRT = 2.6 days) eliminated from the blood. The fraction of total blood clearance that forms II is 0.83 following iv dose of I. The Vss of the less lipophilic metabolite II is somewhat lower (0.36-0.46 liters/kg) than that of the parent drug (0.51-0.56 liters/kg).     

Pharmacokinetics of codeine after parenteral and oral dosing in the rat

The pharmacokinetics of codeine was examined in six male Sprague-Dawley rats following iv bolus (3 mg/kg) and oral (5 mg/kg) codeine in a randomized crossover design. Whole blood concentrations of codeine and its O-demethylated metabolite, morphine, were determined by HPLC with electrochemical detection. Following iv codeine administration, the distribution and elimination are best described by an open two-compartment model. The weight normalized volume of distribution of (Vdarea) and total body clearance (CL) were 5.1 +/- 1.7 liters/kg and 6.2 +/- 1.5 liters/kg/hr, respectively. Mean residence time of codeine averaged 34.1 +/- 6.9 minutes. The ratio of AUCmorphine/AUCcodeine was 0.05 +/- 0.02. The absolute bioavailability of codeine calculated was 8.3 +/- 3.2%, indicating extensive first pass metabolism of codeine. An equivalent amount of codeine and morphine were present in the rat following oral codeine. Thus, the amount of morphine formed following codeine administration depends on the route of codeine administration.     

Metabolism and disposition of diethylene glycol in rat and dog.

The disposition of carbon-14-labeled diethylene glycol (DEG) was determined in rats after oral, iv, and dermal administration, and in dogs after oral administration. Oral administration of DEG to rats was by gavage of 50 or 5000 mg/kg doses, or by provision of 0.3 1.0, and 3.0% in drinking water. Oral doses were well absorbed and excreted primarily (approximately 80%) in urine within 24 hr of administration. Greater than half of the dose was excreted unchanged, with 10-30% of the dose appearing as a single metabolite. The metabolite was isolated and characterized by 13C-NMR to be 2-(hydroxy) ethoxyacetic acid (HEAA). Confirmation of identity was provided by synthesis of HEAA and comparison of its NMR spectra and chromatographic behavior with those of the metabolite. Intravenous doses (50 mg/kg) were eliminated by the same routes and at the same rates as those administered orally and exhibited the same metabolic profile. The fate of oral doses of DEG administered to dogs (500 mg/kg) was similar to that of DEG in rats, with about 30% of the administered dose being excreted in urine as HEAA. DEG slowly penetrated the skin of rats after application of 50 mg to a 12-cm2 area. Only about 10% of the dose was absorbed in 72 hr of exposure, and the absorbed dose appeared to have the same fate as doses administered iv or orally. In all studies with rats, excretion of radiolabel in feces and persistence in tissues were low. The highest percentage of conversion to 14CO2 was 7%, found for doses of 0.3% DEG in drinking water.     

Physiological disposition of CGS 16617 in rat, dog, and man

The disposition and metabolism of CGS 16617 (3-[(5-amino-1-carboxy-1S-pentyl)amino],2,3,4,5-tetrahydro-2-oxo-3S-1H-1 - benzazepine-1-acetic acid), and angiotensin l-converting enzyme inhibitor, were investigated in rats, dogs, and man. In rats, a single oral dose of 10 mg/kg 14C-CGS 16617 afforded peak plasma concentrations of drug between 0.5 and 6 hr of dosing. The AUC was on average 9.6% of that after iv administration of the same dose, indicating low oral absorption of the drug. The apparent volumes of distribution, V1 and Vdss, were 0.45 and 2.5 liters/kg, respectively. Disappearance of the drug from plasma after the iv dose was biphasic, with mean half-lives of 0.5 and 13 hr, respectively, for the lambda 1 and lambda 2 phases. After single iv doses (10 mg/kg) to dogs and rats, 14CGS 16617 was almost exclusively eliminated by the renal route, with urinary recoveries of greater than 90% of dose. The same dose administered orally gave urinary recoveries of less than 10% of the dose in rats and about 15% in the dog. The remainder of the dose was eliminated in the feces. Bile duct-cannulated rats excreted less than 3% of an oral 10 mg/kg dose in the bile, in 24 hr. In man (N = 4), a single oral dose of 100 mg 14C-CGS 16617 resulted in peak plasma concentrations of 0.02-0.07 microgram of drug eq/ml between 4 and 6 hr of dosing. The mean terminal half-life was estimated at 81 hr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Observations on the absorption, distribution, metabolism, and excretion of the dopamine (D2) agonist, quinelorane, in rats, mice, dogs, and monkeys.

Following the oral administration of [14C]quinelorane, a potent and highly specific dopamine (D2) agonist, to rats, mice, and monkeys, the compound was well absorbed, with 50% or more of the radioactivity appearing in the urine within 24 hr. Dogs were pretreated with 22 consecutive daily doses of quinelorane by the oral route (in order to induce tachyphylaxis to the emetic effect) before receiving an iv dose of [14C]quinelorane; just over 80% of the radioactivity was excreted into the urine. A tissue-distribution study in rats receiving a single oral dose of 0.1 mg/kg [14C]quinelorane indicated a widespread distribution of radioactivity, with levels being notably low in the blood and plasma and high in the salivary gland, adrenals, pancreas, and spleen; levels were highest in the stomach and kidneys. The Tmax of radiocarbon in the 22 tissues varied between 0.5 and 6 hr, with some tissues showing a plateau of radioactivity between these time-points. After 8 hr, levels of radioactivity were clearly decreasing, and by 48 hr, background levels were attained. Following the oral and iv administration of quinelorane to rats, the systemic bioavailability was calculated to be 16% and the volume of distribution was found to approximate that of total extracellular water, i.e. approximately 300 ml/kg. Since absorption was satisfactory and the tissue distribution study indicated widespread radioactivity, the low bioavailability may be due to first-pass metabolism. Rats excreted marginally more of the N-despropyl metabolite than unchanged drug into the urine, and dogs excreted principally unchanged quinelorane into their urine, followed by the N-despropyl metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute and subchronic toxicity of a nonsulfhydryl angiotensin-converting enzyme inhibitor

Acute and 1-month toxicity studies with SCH 31846, a nonsulfhydryl anti-hypertensive agent which acts by inhibiting angiotensin-converting enzyme, were initiated to evaluate its toxicity. The oral LD50s in mice and rats were approximately 1.8 and 2.5 g/kg, respectively, while the iv LD50 was approximately 450 mg/kg in mice and 150 mg/kg in rats. Signs of acute toxicity in rats and mice included salivation, hypoactivity, ataxia, prostration, and convulsions. In a 1-month dog study at oral doses of 25, 75, or 150 mg/kg, there was a dose-related increase in emesis between 1 and 2 hr after dosing. Absorption studies showed peak blood concentrations occurring in dogs between 0.3 and 1 hr after dosing. No other noteworthy antemortem changes were observed. In a 1-month rat study at oral doses of 30, 180, or 600 mg/kg, the hematocrit and hemoglobin values of the 600 mg/kg-dosed female rats were slightly but significantly (p less than 0.05) decreased and the blood urea nitrogen was slightly but significantly (p less than 0.05) increased in all SCH 31846-dosed male rats and the 600 mg/kg-dosed female rats. Absorption studies in male rats at doses of 30, 180, and 600 mg/kg indicate that SCH 31846 is well absorbed in rats. The 150 mg/kg-dosed dogs and the 180- and 600 mg/kg-dosed rats had a slight increase in the number of renin-containing granules in the renal juxtaglomerular cells. No other compound-related microscopic changes were observed. These data are similar to data reported for Captopril and suggest that in the dog and rat the toxicity of ACE inhibitors is not dependent upon the presence or absence of a sulfhydryl group.     

Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus macaques

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats (n = 4/sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved C(max) after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and C(max) values following single oral dose administration were not dose proportional; the C(max) value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. Monodesethyl AQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding C(max) values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism of AQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.     

Pharmacokinetics of 4-hydroxycyclophosphamide and metabolites in the rat.

Pharmacokinetics of 4-hydroxycyclophosphamide (4-OHCP), the major active microsomal metabolite of cyclophosphamide (CP), were investigated in the Sprague-Dawley rat following separate iv bolus administrations of CP, synthetic 4-OHCP, and their combination. CP, 4-OHCP, and other metabolites such as phosphoramide mustard, alcophosphamide, and 3-(2-chloroethyl)-1,3-oxazolidin-2-one in rat plasma were simultaneously analyzed using GC/MS and stable isotope dilution techniques. Following iv administrations of 4-OHCP to rats at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg, phosphoramide mustard was found to be the major circulating metabolite followed by alcophosphamide and 3-(2-chloroethyl)-1,3-oxazolidin-2-one. No appreciable amount of nor-nitrogen mustard was detected in circulation. The mean excretion of unchanged 4-OHCP in two rats was 4.1 +/- 0.2% of the administered dose in 24-hr urine. Plasma concentration-time profiles of 4-OHCP declined monoexponentially with a mean half-life and total plasma clearance values of 8.1 min and 81.2 ml/min.kg, respectively. No dose-dependent kinetics were apparent between the 10 and 40 mg/kg doses used. The short half-life of 4-OHCP may be due partly to its degradation in plasma, which was found to be a first-order process in vitro with a half-life of 5.2 min. On the other hand, when CP was administrated to eight separate rats at 20 mg/kg each, the mean apparent elimination half-life for the derived 4-OHCP was 55.4 min as compared to 58.2 min, the mean elimination half-life for the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Toxicokinetics of cinnamaldehyde in F344 rats

The toxicokinetic profile of cinnamaldehyde (CNMA) was investigated in Fischer 344 rats. CNMA was found to be unstable in blood. After iv administration, a large fraction of CNMA was immediately oxidized to cinnamic acid. The biological half-life of CNMA after iv administration was found to be 1.7 hr. After administration by gavage of CNMA at 250 or 500 mg/kg body weight using corn oil as vehicle, the maximum blood concentrations of CNMA were in the order of 1 μg/ml. These low blood concentrations were maintained over a 24-hr period after a dose of 500 mg/kg, which is relatively long considering the short (1.7 hr) biological half-life of CNMA. The estimated oral bioavailability of CNMA was less than 20% for both the 250 and 500 mg/kg doses. No CNMA was present in blood at any time in rats dosed with 50 mg CNMA/kg body weight. Only a small amount of the administered CNMA was excreted in rat urine as free cinnamic acid or β-glucuronide-conjugated cinnamic acid. The majority of CNMA administered orallywas excreted in urine as hippuric acid within 24 hr. The maximum excretion rate occurred at 8 hr after gavage. Hippuric acid recovered in 50-hr urine samples was found to be directly proportional to the oral dose of CNMA.     

异汉防已甲素在大鼠体内的药代动力学及其组织分布

本文报道用反相高效液相色谱法测定生物样品中异汉防己甲素的含量,其最低检出极限可达10 ng/ml。大鼠ⅳ异汉防已甲素的时量曲线属二室开放模型。给大鼠ⅳ本品12.5及25mg/kg后,药物自血浆的消除符合线性动力学,但ⅳ50mg/kg后为非线性动力学。组织分布以肺脏含量最高,血浆最低。大鼠ig异汉防己甲素100及250 mg/kg后,其血浆的时量曲线呈明显的双峰现象。其组织分布以肝脏含量最高,血浆最低。     

The effect of dose on the disposition of lead in rats after intravenous and oral administration

Single doses of lead acetate were administered to 250- to 350-g rats by both iv (0.5–15 mg Pb/kg) and po (1–100 mg Pb/kg) routes, and blood lead concentrations were measured up to 25 days following dosing. The area under the blood lead concentration vs time curve (AUC) after iv dosing increased in proportion to increases in the dose. Total blood lead clearance and renal lead clearance were not related to the magnitude of the injected dose.After oral dosing, blood lead concentrations (and AUC) did not increase proportionately with dose. After a 1 mg/kg po lead dose, the extent of absorption was estimated at 42%; this decreased to 2% when the dose was increased to 100 mg/kg. Lead concentrations in the blood, kidneys, liver, and brain of both adult and suckling rats recovered 24 hr after various single po doses also indicated that the extent of lead absorption decreased substantially with increasing dose. Blood and kidney lead concentrations in adult rats exposed for 14 days to lead via drinking water also were not proportional to the apparent amount of lead ingested. The results are consistent with published in vitro data which suggested that the mechanism for gastrointestinal absorption of lead is largely capacity-limited in adolescent and adult rats. Because blood lead concentrations were not a linear function of the oral dose in the rat, the relationship between oral dose and toxic effects of lead may not be a simple one. This factor should be considered when safe lead exposure levels in man are to be established via extrapolation of data from high levels of exposure.     

Acute and subacute toxicity and efficacy of S-nitrosylated captopril, an ACE inhibitor possessing nitric oxide activities

The toxicity and efficacy of S-nitrosocaptopril (CapNO), a novel vasodilator possessing the capacities of both a nitric oxide donor and an angiotensin converting enzyme (ACE) inhibitor, were examined in rodents. In single-dose acute toxicity studies in ICR mice, the median lethal dose (LD₅₀) for CapNO was 674±94 mg/kg (iv) and 2078±100 mg/kg (po), whereas for oral captopril was 4286±173 mg/kg. S-nitrosoglutathione, containing the same S-nitroso moiety as CapNO, showed an LD₅₀ equal to CapNO when the values were expressed by the mol/kg. The cause of acute death by the high doses of CapNO was lethal hypotension. In the subacute toxicity studies, oral CapNO was well tolerated in normotensive and hypertensive rats at doses up to 500 mg/kg/day for 3 months, except for considerable reductions in food consumption and growth rate observed in the 500 mg/kg/day group. Serum chemistry and hematology tests performed in the subacute toxicity studies revealed no adverse effects of oral CapNO except for a significant decrease in cholesterol levels in hypertensive SHR rat. At autopsy, no histopathological changes in major organs were observed over the subacute period. Administration of a therapeutic dose of CapNO (iv, 250 μg/kg which produced 25% decreases in blood pressure) revealed no changes in the hematological parameters. Subchronic treatment of SHR and SS/Jr rats with oral CapNO (50 mg/kg/day) significantly reduced mean arterial pressure to the normotensive level. Considering the absence of adverse effects of CapNO in the subchronic toxicity study, CapNO appears to be a safe drug for further clinical trials, but particular caution must be taken because it can cause hypotension when overdosed.     

Disposition of exaprolol, a new beta-blocker, in rats

Pharmacokinetics of tritium-labeled exaprolol, 1-(2-cyclohexyl[2,4-3H]-3-isopropylamino-2-propanol, a potent beta-adrenergic blocker, was studied in rats. The assay of the parent drug in plasma and excreta was based on extraction into toluene and TLC. In rats elimination half-lives of exaprolol after iv and oral administration of 26.8 and 40.1 hr, respectively, were found; the bioavailability was 26.7%. After oral administration to rats, the drug was rapidly and completely absorbed. The long retention of exaprolol in tissues of iv injected rats was reflected by the steady-state distribution volume of 59.38 liters/kg and the clearance rate of 1.44 liters/hr/kg. The total 3H excreted in urine within 96 hr after iv or oral administration to rats amounted to 47.9 and 47.1% of dose, respectively, and in feces to 34.2 and 29.8%, respectively. The ratio of 3H-exaprolol to total 3H concentration in plasma, urine, and feces of rats indicated a moderately extensive metabolism of the parent drug. The substance was about 50% bound to human serum albumin. The rat erythrocyte/plasma partition coefficient rose with exaprolol concentration.     

Absorption,bioavailability, and metabolism of para-nonylphenol in the rat

To better interpret the responses to para-nonylphenol (NP; CASRN84852-15-3) in in vivo toxicity studies, including estrogen-like activity, the bioavailability of 14C-radiolabelled NP has been determined in male and female CD rats following either single oral doses of 10 and 100 mg/kg, single i.v. doses of 10 mg/kg, or repeated daily oral doses of 10 mg/kg for up to 14 d. Up to 80% of an oral dose of NP was rapidly absorbed, the remainder being excreted unchanged in faeces. Excretion was largely complete within 24 h of dosing. Following absorption, NP was metabolised in the liver, with the majority of the metabolites excreted in bile, mainly as glucuronide conjugates. Unchanged NP was found only in bile and urine from female rats given a 100 mg/kg dose, indicating that metabolic saturation occurred. Following repeated dosing, steady state was reached within 7 d. There was no evidence of significant accumulation into tissue compartments nor of a significant change in clearance or the metabolite profiles in urine. These data suggest that the estrogen-like effects observed in toxicity studies with female rats at oral NP doses of approximately 50 mg/kg/d and greater are a result of the increased bioavailability of NP which occurs following metabolic saturation.     

Comparative pharmacokinetics of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (AZddU) in mice

The pharmacokinetics of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (AZddU, CS-87), active anti-HIV compounds, were characterized in uninfected mice. Sensitive and specific HPLC techniques were used to quantitate AZT and AZddU concentrations in serum and brain homogenates following iv doses of 50 mg/kg and 250 mg/kg. The pharmacokinetic parameters of t1/2, CIt, and Vss were similar for both compounds at each dose; however, CIt and Vss decreased at the higher dose, indicating a dose dependency. At the 50 mg/kg doses, the CIt of AZddU and AZT was 1.27 liters/hr/kg and 1.38 liters/hr/kg, respectively, which is analogous to the clearance value of AZT observed in humans. Brain/serum concentration ratios for AZddU tended to be greater than those obtained for AZT and were significantly different at the 50 mg/kg dose, being 0.234 +/- 0.282 for AZddU and 0.064 +/- 0.025 for AZT.     

Effects of dose, sex, and age on the disposition of alendronate, a potent antiosteolytic bisphosphonate, in rats.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of a variety of bone disorders. Earlier studies from this laboratory have demonstrated that systemically administered drug was rapidly taken up by bone tissue or excreted by the kidneys. Approximately 60 to 70% of the dose was taken up by the bone, and 30 to 40% was excreted in the urine. The purpose of this study was to determine the effects of dose, sex, and age on the disposition kinetics of alendronate using rats as an animal model. No evidence of saturation of drug uptake by the bone was observed in young rats when small, repetitive doses of alendronate were administered every 3 days for 21 days (total 35 mg/kg iv). However, less than proportional uptake by the bone was observed in young rats when single iv doses exceeded 10 mg/kg. Overall, a 500-fold increase in dose resulted in a 350-fold increase in drug concentration in bone. Nonlinear uptake of alendronate by bone was accompanied by simultaneous accumulation in noncalcified tissues at high doses. Less than 1% of the dose was found in noncalcified tissues at 24 hr after low doses (1 mg/kg iv), and 25% after high doses (30 mg/kg iv). Following iv administration, uptake of alendronate by the bone was lower in senescent rats than in young rats by a factor of 2 to 3. Bone uptake was lower in female rats than in male rats by about 30 to 40%, but this sex difference was only observed at low doses and in young rats.     

Pharmacokinetics of the anti-AIDS drug 2',3'-dideoxyinosine in the rat

The pharmacokinetics of 2',3'-dideoxyinosine (ddlno) was examined in the male Fischer 344 rat using reversed phase HPLC with UV and radiochemical detection. Following iv doses of 12, 25, and 100 mg/kg, the parent drug was rapidly eliminated from plasma (mean residence time, 6.3 min; systemic clearance, 64 ml/min/kg). The mean terminal elimination half-life was 28 min and the volume of distribution at steady state was 0.39 liter/kg. Orally administered [3H]ddlno (100 mg/kg) was not significantly bioavailable in the rat, with only 8-11% of the dose absorbed as the parent compound over a 2 hr period. Peak plasma drug concentrations occurred 10 to 20 min following oral administration. Solution stability data suggested that ddlno was unstable at gastric pH (pH 1, t1/2 less than 30 sec). However, elevation of gastric pH with sodium bicarbonate prior to oral administration of ddlno was not effective in increasing the bioavailability of the parent drug. The drug and its metabolic products were extensively distributed into rat tissue 48 hr after iv or oral administration. Following iv infusion of [3H]ddlno to steady state conditions, the highest tissue-to-plasma ratios of radioactivity were found in the kidney (2.2), liver (1.7), and spleen (1.5). Renal clearance accounted for 99% of the eliminated dose. Liver perfusion studies showed that ddlno was not subject to significant hepatic clearance (less than 10%) and that the metabolism was not inducible with phenobarbital.     

Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: Contribution of intestinal first-pass effect to low bioavailability in rats.

The pharmacokinetics of DA-6034 in rats and dogs and first-pass effect in rats were examined. After intravenous administration, the dose-normalized AUC(0-infinity) values at 25 and 50mg/kg were significantly smaller than that at 10mg/kg. This could be due to significantly slower Cl(r) values than that at 10mg/kg, possibly due to saturated renal secretion at doses of 25 and 50mg/kg. After oral administration, the dose-normalized AUC(0-12h) values at 50 and 100mg/kg were significantly smaller than that at 25mg/kg, possibly due to poor water solubility of the drug. The low F-value (approximately 0.136%) of DA-6034 at a dose of 50mg/kg in rats could be due to considerable intestinal first-pass effect (approximately 69% of oral dose) and unabsorbed fraction from the gastrointestinal tract (approximately 30.5%). The effect of cola beverage, cimetidine, or omeprazole on the AUC(0-24h) of DA-6034 was almost negligible in rats. Pharmacokinetic parameters of DA-6034 after intravenous and oral administration at various doses were dose-independent in dogs. DA-6034 was not accumulated in rats and dogs after consecutive 7 and 28 days oral administration, respectively. The stability, blood partition, and protein binding of DA-6034 were also discussed.     

Assessment of efficacy of activated charcoal for treatment of acute T-2 toxin poisoning

"Superactive" charcoal was assessed for efficacy in decreasing the lethality of both oral and parenteral exposure to T-2 toxin, a fungal metabolite which can cause death or illness upon ingestion. In vitro binding studies, analyzed using the Langmuir adsorption isotherm, showed that activated charcoal had a maximal binding capacity of 0.48 mg toxin/mg charcoal and a dissociation constant of 0.078 mg charcoal/l. In vivo, orally administered, activated charcoal was assessed for treatment of acute oral or parenteral exposure to T-2 toxin in mice. Following oral toxin administration (5 mg/kg), untreated mice showed only 6% survival after 72 hr. Charcoal treatment (7 g/kg,po) either immediately or 1 hr after toxin exposure resulted in significant improvement in survival with values of 100% and 75%, respectively. Following parenteral toxin exposure (2.8 mg/kg, sc), untreated and charcoal-treated (7 g/kg, po) mice showed 50% and 90% survival, respectively, after 72 hr. LD50 value for T-2 toxin, determined at 96 hr after intoxication, increased significantly from 2 mg/kg for untreated controls to 4.5 mg/kg for activated charcoal treatment.