Time-dependent, plasma-sulfate-independent kinetics of salicylamide in dogs (original) (raw)
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AJP: Regulatory, Integrative and Comparative Physiology, 2005
Electrospray tandem mass spectrometry was used to determine steady-state serum and urinary inorganic sulfate and sulfate ester kinetic profiles of nine normal men after intravenous injection of the stable isotope sodium [ 34 S]sulfate. Sulfate ester appearance was traced by eliminating inorganic sulfate from samples, followed by hydrolysis of sulfate esters to inorganic sulfate for analysis. Whole body inorganic sulfate turnover in steady state was calculated using standard tracer techniques. Rate of appearance and disappearance of inorganic sulfate was 841 Ϯ 49 mol/h. Average urinary inorganic sulfate excretion was 609 Ϯ 41 mol/h, and the whole body sulfation rate (total rate of disappearance minus rate of urinary excretion) was 232 Ϯ 36 mol/h. Tracer-labeled sulfate esters appeared in serum and urine within 1 h of tracer injection. The kinetics of inorganic sulfate and sulfate esters were linked by means of a compartmental model. The appearance and excretion of sulfate esters accounted for ϳ 50% of the total sulfation rate. These results indicate that human whole body sulfation accounts for ϳ 27% of inorganic sulfate turnover and that extracellular inorganic sulfate is an important pool for intracellular sulfation. A substantial fraction of newly synthesized sulfate esters promptly enters the extracellular space for excretion in the urine.
Concurrent determination of hepatic bioavailability of salicylamide by three techniques in the dog
Journal of Pharmaceutical Sciences, 1989
0 Three methods of measuring hepatic first-pass metabolism of salicylamide in dogs that had undergone portacaval transposition were compared. The drug in both its radiolabeled (0.74 MBq) and unlabeled (20 mg/kg) forms was infused concurrently into forelimb and hindlimb veins, respectively. Because of the transposition, drug from the hindlimb is subject to first-pass metabolism in the liver. Bioavailability is a complementary measure of the extent of this metabolism. The three methods of determining bioavailability were continuous withdrawal of blood to determine the ratio of the areas under the plasma concentration versus time curves, ratio of specific activities in plasma after all the drug had been administered, and the conventional method, measurement of the ratio of areas determined from sequential plasma concentrations. The three techniques were found to give virtually identical values for bioavailability. Each method has its own advantages, limitations, and possible applications. The continuous withdrawal technique is potentially most applicable for drugs with short half-lives. The ratio of specific activities may be the preferred method for drugs with long half-lives. The conventional method is limited by the number of samples needed, but is potentially useful under those conditions in which data following test and intravenous routes of administration are available.
Pharmacokinetics of sulphadimidine in normal and febrile dogs
Journal of Veterinary Pharmacology and Therapeutics, 1982
Pharmacokinetic parameters which describe the distribution and elimination of sulphadimidine were determined in normal dogs and dogs in which fewer was produced by an intravenous injection of escherichia and staphylococcal species of bacteria. Sulphadimidine was injected as a single intravenous bolus at the dose of 100 mg/kg and the kinetics of the drug were described in terms of the biexponential expression: Cp = Ae-alpha t + Be-beta t. The distribution half-times of the drug were 1.52 h in the normal and 0.81 h in the febrile dogs. The drug distribution was significantly more rapid (P less than 0.05) in febrile than in normal dogs. Average +/- SD values for the half-lives of the drug were 16.2 +/- 5.7 h in normal and 16.7 +/- 4.7 h in the febrile dogs. The apparent volume of distribution (V'd(area)) was 628 +/- 251 ml/kg in the normal dogs, and was not statistically different from 495 +/- 144 ml/kg in the febrile dogs. The volume of the central compartment (V'c) was 445 +/- 55 ml/kg in normal dogs and this was significantly higher (P less than 0.01) than the V'c of 246 +/- 72 ml/kg in the febrile dogs. The body clearance was 22.4 +/- 4.8 and 20.2 +/- 3.6 ml/hour . kg in the normal and febrile dogs, respectively. The investigation revealed that the dosage regimen of sulphadimidine did not differ significantly between normal and febrile dogs.
Pharmacokinetic model for salicylate in cerebrospinal fluid, blood, organs, and tissues
Journal of Pharmaceutical Sciences, 1978
o The developed pharmacokinetic model, an extension of the Bischoff-Dedrick model, simultaneously predicts the kinetic behavior of salicylate in cerebrospinal fluid, blood, organs, and tissues. The model, which is entirely different from conventional compartment models, is derived from basic considerations of drug distribution with biochemical and physiological meaning. The dog was studied at three different dosages of salicylate: therapeutic, moderate intoxication, and severe intoxication. The predicted kinetics of salicylate in cerebrospinal fluid, blood, plasma, liver, muscle, and adipose tissue by the model agreed well with the experimental data. The effectiveness of hemoperfusion treatment for the severely intoxicated dog by albumin-coated activated carbon and its effect on the kinetic behavior of salicylate in cerebrospinal fluid, blood, organs, and tissues were studied. The model was also applied to predict the kinetic changes of salicylate in the body during and after the extracorporeal treatment. The predicted results also agreed with the experimental data.
Pharmacokinetics and urinary excretion of sulphadimidine in sheep and goats
Journal of Veterinary Pharmacology and Therapeutics, 1979
Pharmacokinetics and urinary excretion of sulphadimidine were determined in sheep and goats following a single intravenous injection (100 mg/kg). The disposition of the drug was described in terms of exponential expression: Cp=Be-βt. Based on total (free and bound) sulphonamide level in plasma, pseudo-distribution equilibrium was rapidly attained and the half-life for elimination was 3.88 ± 0.64 h and 4.00 ± 0.34 h in sheep and goats, respectively. Body clearance, which is the sum of all clearance processes was 88 ± 19 and 55 ± 4 ml/kg/h in sheep and goats. Based on this study a satisfactory intravenous dosage regimen might consist of 100 and 60 mg sulphadimidine/kg body wt for sheep and goats and should be repeated at 12 h intervals. The influence of disease conditions on predicted plasma levels remain to be verified experimentally. Three-quarters of an intravenously injected dose of sulphadimidine was excreted in the urine of sheep and goats within 24 h of administration. The drug was mainly excreted as free amine while acetylated drug constituted 7 and 8% of total drug content in the urine of sheep and goats, respectively.
Drug Metabolism and Pharmacokinetics, 1991
Salazosulfapyridine (Sulfasalazine, SASP, 2-hydroxy-5-[[4-[(2-pyridinylamino) sulfonyl I phenyll azol benzoic acid) labelled with 14C in the carboxyl group and with 3H in chemically as well as metabolically stable positions in the benzenesulfonyl ring was administered either intravenously or orally to male and female rats in order to study the plasma pharmacokinetics of SASP and the plasma profiles of the metabolites. After intravenous administration SASP was eliminated rapidly from plasma with a half-life (t1/2) of 8min. The volume of distribution (Vdss) of SASP was 0.21/kg and total clearance (CLtot) was 18m1/min x kg. After oral administration, SASP was present in plasma mainly during the first 4 hours. The time for maximal concentration (Tmax) varied for SASP between 1-3 hours, for 14C, corresponding to 5ASA metabolites, between 3-10 hours and for 3H, corresponding to sulfapyridine metabolites, be tween4-12 hours. The inter-individual variation was considerable. The bioavai lability of SASP was 9% and independent of the dose. The maximal concentr ation(Cmax) and area under the curve (AUC) increased proportionally with the dose. The absorption of SASP was not influenced by fasting overnight. There was a clear sex difference in the metabolism of SASP. The plasma concentration of sulfapyridine metabolites in female rats was twice that in male rats. No hydroxylated metabolites were found in female rat plasma, whereas in the male rats, the hydroxylated sulfapyridine metabolites were the major metabolites.
Yakubutsu dōtai, 1991
Repeated daily oral doses of [14C, 3H]salazosulfapyridine 50mg/kg b.w. was given to male and female rats during 21 days to investigate the absorption, tissue distribution and elimina tion of SASP and metabolites. The peak plasma level of radioactivity was slightly increased for both 3H and 14C during repeated administration although the increase was not statistically significant. The elimination rate from plasma was similar after the last 21st dose as after a single dose. Thus the 24 hour plasma level was not increased. The concentration of unchanged SASP in plasma was too low to be measurable by liquid chromatography. There was no significant binding of radioactivity to the erythrocytes after the first dose, but after repeated doses some distribution of 14C to the blood cells was seen. The dominating picture of the tissue distribution was that most of the radioactivity remained in the gastrointestinal tract. Even 96 hours after the last dose, when only trace amounts of radioactivity remained, the highest radioactivity was found in caecum. Except for the gastrointestinal tract, the concentration of radioactivity was initially lower in the tissues than in plasma and was dominated by 3H. The concentration of 3H in tissues in relation to the plasma concentration was not changed during the repeated administration. However, the 14C concentration increased. The tissue distribution was also studied by autoradiography and image analysis after the same pretreatment as above and with a final high dose of [3H]SASP. The time points stud ied were 4, 16, and 96 hours after the last given dose. The highest uptake was noticed in the connective tissues, the lung, the kidney, the epididymis, the penis and the pituitary gland. With whole body autoradiography the tissue distribution was also studied 5 min, 1 hour and 16 hours after an i.v. injection of 14C_or 3H-labelled SASP in pregnant rats, which had been pretreated orally in 10 days with unlabelled SASP. The aim of this study was to inves tigate whether such a pretreatment caused an altered distribution pattern, compared to that after an i.v. single dose, in the fetal and placental tissues. The fetal concentration did not rise significantly. However, the maternal tissues indicated a slight increase for most tissues. No changes were found in the excretion of radioactivity or in the metabolite pattern in urine and faeces during the administration. Neither did a consecutive administration of SASP cause any induction of hepatic drug metabolizing enzymes, such as cytochrome P-450, cyto chrome b5, aminopyrine demethylase and aniline hydroxylase.
Comparative pharmacokinetics of salicylate in camels, sheep and goats
European Journal of Drug Metabolism and Pharmacokinetics, 2003
This study compared some pharmacokinetic parameters of DL-lysine-acetyl salicylate administered intravenously (i.v.) and intramuscularly (i.m.) at a dose of 20 mg/kg in camels, sheep and goats. The data was analyzed using a non-compartmental model. In camels, sheep and goats given the drug i.v., the t 'h values were 43.1, 31.2 and 27.3; the clearance (CI) values were 203.7, 261.1, and 280.4 ml/h/kg, while the area under the curve (AVC) were 100.1, 106.9 and 110.5 rng.h/L, respectively. In camels, sheep and goats given the drug by the i.m, route the mean peak plasma concentration (CmaX> were 0.94,1.44 and 1.74 mg/ml, and the time to reach C max (t max ) were 2.94, 2.57 and 2.43h, respectively. The t'h values were 48.9,38.2 and 36.0 min; the clearance (Cl) values were 261.3,297.4 and 306.4 ml/h/kg, while the area under the curve (AVC) were 101.6, 117.3 and 123.7 mg.h/L, respectively. The drug bioavailability (F) in camels, sheep and goats were 71.3, 78.4 and 79.4% respectively. These findings suggest that the rate of absorption and elimination of the salicylate is slower in camels than in sheep and goats.