Autoradiographic and scintillationspectrographic studies of 14C-zolimidine in rats after i.v. and oral application (author's transl)

The relative distribution of radioactivity after i.v. (5 mg/kg) and oral (25 mg/kg) application of 14C-Zolimidine [2-(p-methyl-sulfonylphenyl)-imidazo-(1,2-a)-pyridine-2-14C] was examined in male rats by whole-body autoradiography and scintillation fluid spectrometry. 14C-Activity was remarkably concentrated in the stomach of i.v. treated animals, probably as a result of secretion from the pyloric and/or fundic part of the mucous membrane. 14C-Zolimidine also accumulated in the aortic vascular walls, the adrenal gland, and in the excretory organs, liver, kidney, and intestine, after both routes of drug administration. Much less radioactivity could be measured in brain and spinal cord. The estimation of nearly 80% gastrointestinal absorption of 14C-zolimidine and the suggestion of one or more metabolites were in accordance with previously reported results. The elimination of radioactivity from brain occurred more rapidly than from other organs. No striking results were found in the reproductive organs of the rats.     

Disposition of [14C]avitriptan in rats and humans

Avitriptan is a new 5-HT1-like agonist with abortive antimigraine properties. The study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of avitriptan after intravenous (iv) and oral administrations of [14C]avitriptan in rats and oral administration of [14C]avitriptan in humans. The doses used were 20 mg/kg iv and oral in the rat, 10 mg iv in humans, and 50 mg oral in humans. The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring at 0.5 hr postdose. Absolute bioavailability was 19.3% in rats and 17.2% in humans. Renal excretion was a minor route of elimination in both species, with the majority of the dose being excreted in the feces. After a single oral dose, urinary excretion accounted for 10% of the administered dose in rats and 18% of the administered dose in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats. Avitriptan was extensively metabolized after oral administration, with the unchanged drug accounting for 32% and 22% of the total radioactivity in plasma in rats and humans, respectively. Plasma terminal elimination half-life was approximately 1 hr in rats and approximately 5 hr in humans. The drug was extensively distributed in rat tissues, with a tendency to accumulate in the pigmented tissues of the eye.     

The influence of acute diazepam pretreatment on the action and disposition of [14C]pentobarbital in rats

Diazepam (DZP) pretreatment (100mg/kg, ip) of rats 6 h before pentobarbital administration (45 mg/kg, ip) prolonged the barbiturate-induced narcosis. The concentrations of [14C]pentobarbital and total pentobarbital derivatives in blood or brain showed no differences between control and DZP-pretreated animals. The brain and blood concentrations of pentobarbital, when measured at a time corresponding to the respective arousal times from pentobarbital narcosis, were lower in the DZP-pretreated group. These results indicate that acute DZP pretreatment increases the sensitivity of the rat brain to pentobarbital rather than inducing changes in the disposition of the barbiturate.     

14C]leucine incorporation into proteins of pancreatic juice in rats fed soya-bean flour

1. The effect of a diet containing a trypsin inhibitor on the incorporation of radioactively labelled leucine into the pancreatic proteins secreted during stimulation with cholecystokinin-pancreozymin (CCK) was studied in rats. 2. The total output of protein was significantly greater in the rats given raw soya-bean flour (RSF) compared with those given heat-inactivated soya-bean flour (HSF) (controls) in response to the sub- and supramaximal stimulation with CCK, but similar responses were obtained to maximal stimulation with CCK. Total protein output decreased continuously with time after reaching peak values at 90--120 min after the start of stimulation with CCK. 3. The total output of radioactively labelled protein in RSF-fed rats was not different from that of the controls with sub- and supramaximal dose rats of CCK, but was significantly lower than that of the controls in response to the dose rate of CCK which produced maximal rates of pancreatic secretion. 4. The specific activity of radioactively labelled protein increased continuously, while the output attained a constant rate during stimulation with all doses of CCK. 5. We concluded that feeding the trypsin inhibitor-containing diet led to increased secretion of stored pancreatic protein, while secretion of newly synthesized protein was not altered. During the course of prolonged stimulation with CCK, irrespective of diet, there was increasing secretion of the newly synthesized protein compared with the pre-existing stored proteins of the pancreas, it was unable to compensate for the decreased secretion of pre-formed protein.     

Comparative pharmacokinetics of four cholinesterase inhibitors in rats

Pharmacokinetics of a very short-acting, a short-acting and two long-acting cholinesterase (ChE) inhibitors, edrophonium, neostigmine, pyridostigmine and ambenonium, respectively, were compared to elucidate the major determinant of their pharmacokinetics. No dose-dependency in pharmacokinetic behavior was observed within the range of 2-10 mumol/kg for edrophonium, 0.5-2 mumol/kg for pyridostigmine, 0.1-0.5 mumol/kg for neostigmine and 0.3-3 mumol/kg for ambenonium, respectively. Neostigmine has the shortest elimination half-life, and edrophonium, pyridostigmine and ambenonium follow in that. Four ChE inhibitors have similar Vdss values within the range of 0.3-0.7 l/kg, which is similar to the muscle/plasma concentration ratio of these drugs. The liver or kidney to plasma concentration ratio of all ChE inhibitors at 20min after i.v. administration ranged from 5 to 15. Small distribution volumes estimated from the plasma concentration profiles may reflect the distribution to muscle and to the extracellular space of other organs/tissues, while the rapid disappearance of ChE inhibitors from plasma may reflect the concentrative uptake to the liver and kidney.     

Absorption, distribution, and excretion of [14C]patulin by rats

Adult rats of both sexes were given a single oral dose of [14C] patulin and were sacrificed at various time intervals from 4 hr to 7 days following administration of the mycotoxin. Two groups of rats were employed; the treated group had been exposed to daily oral doses of unlabeled patulin (dissolved in pH 5.0 citrate buffer) in utero and for 41-66 wk after weaning, while the controls were given the buffer only throughout gestation and for 38-81 wk after weaning. Approximately 49% of the administered 14C radioactivity was recovered from feces and 36% from urine within 7 days after dosing. Most of the excretion of labeled material occurred within the first 24 hr. All of the 14C activity detected in the urine samples was either metabolites and/or conjugates of the original [14C]patulin. About 1-2% of the total radioactivity was recovered as 14CO2 from expired air. Carbon-14 radioactivity in various tissues and organs was determined throughout the 7 day period; the most significant retention site was the red blood cells.     

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.     

The incorporation of [14C]glucosamine into dolichol diphosphate N-acetyl[14C] glucosamine by unbroken liver cells in culture

Urinary testosterone and epitestosterone were assayed in 60 men: 7 normals and 53 patients with chronic prostatitis (of these 8 patients had prostatis free of complications, 45 had prostatitis with disturbances of generative and copulative functions). In 73.1% of patients considerable reduction of testosterone excretion was revealed. Reduction of testicular endocrine function is in direct correlative dependence on severity of clinical symptoms, duration of disease and form of chronic prostatis. Disturbances of genital hormone metabolism are of considerable importance in case of chronic prostatitis and its complications.     

Pharmacokinetic study in rats after single intravenous and oral administrations of [14C]-ITF-296

Fifteen mycoplasma-free chickens were contact exposed to five chickens that had been experimentally infected with one of three different strains (two field strains and one laboratory strain) of Mycoplasma synoviae (MS). Culture and polymerase chain reaction (PCR) were positive by 3 days postinoculation (PI) in the experimentally infected birds. Lateral transmission was found by 7-14 days postexposure. Positive serum plate agglutination (SPA) results were detected 3-4 wk after positive culture and/or PCR in individual birds. By 42 days PI, all the birds in the groups exposed to field strain K1858 or K3344 had become infected as determined by culture and PCR, whereas only half of the birds in the group exposed to laboratory strain WUV1853 had become infected. Because of the unanticipated lack of seroconversion to hemagglutination inhibition (HI) and enzyme-linked immunosorbent assay (ELISA) in infected chickens, the study was extended. Each group was split into two groups of 10 birds each, one of which was vaccinated with a live B1/LaSota Newcastle disease (ND) vaccine virus to determine if a viral respiratory challenge might incite a stronger antibody response to the mycoplasma infection. All the birds were tested for seroconversion 14 and 21 days later. Of the birds vaccinated for ND, a slightly greater number were MS positive by SPA than the nonvaccinated birds. This effect was not present 21 days after vaccination, and there was no significant difference in the MS HI results from these groups, suggesting that the viral respiratory infection had little direct impact on seroconversion. The virulent field strain (K3344) elicited a stronger MS antibody response than the other strains. All results from the MS ELISA were negative in all groups through 9 wk. Positive results from PCR analysis correlated well with culture results, whereas serologic tests did not detect MS infection for several weeks. Monitoring programs solely dependent on seroconversion may be inadequate for diagnosis and control of mycoplasma infections.     

Circadian changes in the pharmacokinetics and pharmacodynamics of azosemide in rats

The circadian changes in the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg(-1)) to rats at 1000 or 2200 h. After intravenous administration of azosemide the percentage of the dose excreted in 8-h urine as unchanged azosemide was significantly higher in the 1000 h group than in the 2200 h group (41.7 compared with 28.9%) and this resulted in a significant increase in 8-h urine output (84.7 compared with 36.6 mL/100 g). After intravenous administration the time-averaged renal clearance (CLR) of azosemide was significantly faster (2.86 compared with 1.76 mL min(-1) kg(-1)) and urinary excretion of sodium (46.4 compared with 25.9 mmol/100 g) and chloride (35.6 compared with 18.8 mmol/100 g) increased significantly in the 1000 h group. However, after oral administration, the percentages of oral dose of azosemide excreted in 8-h urine as unchanged azosemide were significantly higher (1.88 compared with 0.67%) and the CL(R) of azosemide was significantly faster (3.64 compared with 0.79 mL min(-1) kg(-1)) in the 2200 h group. This could be at least partly because of increased absorption of azosemide from the gastrointestinal tract in the 2200 h group; the percentages of oral dose of azosemide recovered from the gastrointestinal tract in 8 h as unchanged azosemide was significantly smaller (5.7 compared with 13.2%) in the 2200 h group. The pharmacodynamic parameters of azosemide were not significantly different after oral administration of the drug to both groups of rats. If these data could be extrapolated to man, the intravenous dose of azosemide could be modified on the basis of circadian time.     

Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats

We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t(1/2)) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t(1/2) of the dexamethasone pretreatment group (14.4+/-0.7 min) was significantly shorter than that of the prednisolone group (20.9+/-1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.     

The pharmacokinetics and metabolism of heptapeptide--a prospective synthetic analog of tuftsin with psychostimulating action in rats

The lymphocyte blast transformation test (LBTT) with three tuberculin dilutions was used to examine 190 patients with varying pulmonary tuberculosis activity, of them 63 patients received chemotherapy. According to the blast formation in the patients' cultured peripheral blood cells by three tuberculin dilutions, a correlation was found between the clinical manifestations of the process and the functional activity of T lymphocytes. Thus, the greatest percentage (500 TU) of blasts in LBTT per mean PPD dose was detectable in patients with low LBTT results by three tuberculin dilutions with positive dynamics during chemotherapy. With further positive dynamics, the proportion of blasts in the cultured peripheral blood cells was highest per high PPD doses (5000 TU). On the contrary, patients with progressive tuberculosis displayed a oppositely directed phasic pattern.     

The pharmacokinetics of poliosm

Functional features of type Br?nemark implants are compared with those of type IMZ implants. The problem of determining optimal stiffness characteristics of type IMZ implants has been solved by means of linear programming. The conclusion was made on considerable improvement in distribution of loads when type IMZ osseointegrated implants are used as supporting elements in the denture.     

Synthesis of UDP-N-[1-14C]acetyl D-glucosamine and UDP-N-[1-14C]acetyl-D-galactosamine from [1-14C]acetate

Procedures for the preparation of UDP-N-[1-14C]acetyl-D-glucosamine and UDP-N-[1-14C]acetyl-D-galactosamine with very high specific activities are described. The overall yield based on the amount of [1-14C]acetate used is greater than 80%. The N-acetyl-D-glucosamine-alpha-1-phosphate used in this synthesis is prepared by phosphorylation of tetraacetyl-D-N-acetylglucosamine with crystalline phosphoric acid. N-acetyl-D-glucosamine-alpha-1-phosphate is then deacetylated in anhydrous hydrazine with hydrazine sulfate as a catalyst. D-glucosamine-alpha-1-phosphate is N-acetylated with [14C]acetate using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as the coupling agent. The acetylated product is coverted to the UDP derivative with yeast UDP-N-acetyl-D-glucosamine pyrophosphorylase. UDP-N-[1-14C]acetylgalactosamine is prepared by acetylation of UDP-galactosamine using [1-14C]acetate and N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline. UDP-galactosamine is prepared enzymatically using galactokinase and galactose-1-phosphate uridyltransferase. The labeled products, isolated and characterized by ion-exchange and paper chromatography, were active as substrates in glycosyl transferase systems.     

The pharmacokinetics and metabolism of 14C/13C-labeled ortho-phenylphenol formation following dermal application to human volunteers

1. The pharmacokinetics and metabolism of uniformly labeled 14C/13C-ortho-phenylphenol (OPP) were followed in six human male volunteers given a single 8 h dermal dose of 6 microg OPP/kg body weight formulated as a 0.4% (w/v) solution in isopropyl alcohol. The application site was covered with a non-occlusive dome allowing free movement of air, but preventing the loss of radioactivity due to physical contact. At 8 h post-exposure the non-occlusive dome was removed, the dose site was wiped with isopropyl alcohol containing swabs and the skin surface repeatedly stripped with tape. Blood specimens, urine, and feces were collected from each volunteer over a 5 day post-exposure period and were analyzed for radioactivity and metabolites (urine only). 2. Following dermal application, peak plasma levels of radioactivity were obtained within 4 h post-exposure and rapidly declined with virtually all of the absorbed dose rapidly excreted into the urine within 24 h post-exposure. A one-compartment pharmacokinetic model was used to describe the time-course of OPP absorption and clearance in male human volunteers. Approximately 43% of the dermally applied dose was absorbed through the skin with an average absorption half-life of 10 h. Once absorbed the renal clearance of OPP was rapid with an average half-life of 0.8 h. The rate limiting step for renal clearance was the relatively slower rate of dermal absorption; therefore the pharmacokinetics of OPP in humans was described by a 'flip-flop' single compartment model. Overall, the pharmacokinetics were similar between individuals, and the model parameters were in excellent agreement with the experimental data. 3. Approximately 73% of the total urinary radioactivity was accounted for as free OPP, OPP-sulfate and OPP-glucuronide conjugates. The sulfate conjugate was the major metabolite (approximately 69%). Therefore, total urinary OPP equivalents (acid-labile conjugates+free OPP) can be used to estimate the systemically absorbed dose of OPP. 4. The rapid excretion of OPP and metabolites into the urine following dermal exposure indicates that OPP is unlikely to accumulate in humans upon repeated exposure. Based on these data, blood and/or urinary OPP concentration (acid-labile conjugates) could be utilized to quantify the amount of OPP absorbed by humans under actual use conditions.     

The degradation of [14C]molinate in soil under flooded and nonflooded conditions

The degradation of [14C]molinate in soil under flooded and nonflooded conditions was investigated. In laboratory studies, 50 percent of the applied molinate was lost in 3 weeks under moist soil conditions, while under flooded conditions, dissipation was reduced to 50 percent loss in 10 weeks. Analysis for molinate and its degradation products in the soil and flood water showed that under flooded conditions very little breakdown of molinate occurred, and volatilization was the primary mode of dissipation. However, under nonflooded conditions, hydroxylation of the azepine ring and further oxidation to the respective ketones occurs. Oxidation to form the sulfoxide, cleavage to yield the imine, and acetylation of the imine are also proposed. Other pathways appear to involve desethylation to produce a free thiocarbamic acid derivative followed by S-methylation as well as carboxylation of the S-ethyl group.