Search PubMed⌕ Search

Biomedical subjects

T B Vree

Publications and source records attributed to T B Vree.

At least 127 records · Page 7Linked to original sources
PubMed1990

Oral dosage regimen in the nonlinear pharmacokinetics of sulphadimethoxine in pigs.

An oral high dosage regimen of sulphadimethoxine (SDM) was examined in pigs. The dose (50 mg/kg) in the therapeutic range, showed nonlinear pharmacokinetics, and administered by drench once a day for 4 days. The unbound plasma concentration-time profile was compared with that of the dosage regimen based on nonlinear pharmacokinetics, where a pharmacokinetic model and parameters were used except for the first order absorption rate constant (ka) and bioavailability (F). F and ka were obtained from oral and intravenous administration of 20 and 10 mg/kg of SDM. The unbound plasma concentration was observed almost within the setting range by the dosage regimen through the experimental period. This result suggested that the dosage regimen, based on the nonlinear pharmacokinetic model, resulted in an appropriate effect in the clinical use.

Absorption↗
PubMed1990

The role of plasma protein binding on the metabolism and renal excretion of sulphadimethoxine and its metabolite N4-acetylsulphadimethoxine in pigs.

The effects of plasma protein binding on the elimination of sulphadimethoxine (SDM) were examined after intravenous administration of 6.25, 12.5, 25, 50, 100 and 150 mg/kg to pigs. At an early stage of the experiment, the animals were anaesthetised by inhalation of enflurane to obtain a more exact relationship between plasma concentration and the renal excretion. SDM and its acetylated conjugate, N4-acetylsulphadimethoxine (N4-SDM) were detected in plasma and urine of all animals, and the recovery of the doses was almost complete in two animals with negligible renal excretion of SDM. The percentages of plasma protein binding of SDM and N4-SDM were almost similar, and ranged from 30 to 95%, depending on the plasma concentration. The metabolic clearance of SDM by acetylation increased when the plasma protein binding decreased. These results suggested that the main elimination route of SDM in pigs is acetylation, and that the plasma protein binding can have a large effect on the elimination of SDM in pigs. The effect of plasma protein binding on the renal clearance of SDM was not so evident, because urine pH had a much greater effect on it. The deacetylation of N4-SDM was detected after 25 mg/kg intravenous administration of N4-SDM, which suggests that the metabolic clearance of SDM is part of an acetylation-deacetylation equilibrium. Saturation of the active tubular reabsorption of SDM and of the active tubular secretion of N4-SDM was also suggested after higher doses of SDM.

Acetylation↗
PubMed1990

The effect of multiple-dose oral lomefloxacin on theophylline metabolism in man.

Single-dose plasma pharmacokinetics of theophylline (6 mg/kg intravenously) and renal excretion of theophylline and its metabolites, resulting from 8-oxidation and N-demethylation, were investigated in eight healthy volunteers before and at day 3 of concomitant oral administration of the quinolone derivative lomefloxacin (400 mg twice daily). Plasma samples were collected until 24.5 h, and urine samples were collected until 72 h after theophylline administration. The concentrations of theophylline and the major metabolites, resulting from N-demethylation and 8-oxidation, were measured utilizing a high-pressure liquid chromatography (HPLC) technique. No significant changes in theophylline half-life, volume of distribution, protein binding, total body clearance, or renal clearance were noted. In addition, renal excretion of unchanged theophylline, the products of the N-demethylation, 3-methylxanthine, and 1-methyluric acid, and the product of the 8-oxidation, 1,3-dimethyluric acid, were not altered by simultaneous administration of lomefloxacin. Orally administered lomefloxacin is absorbed quickly and to a high extent. During administration of 400 mg twice daily, plasma concentrations reached are well above minimum inhibitory concentration (MIC) values of pathogens that are frequently isolated in lower respiratory tract infections. This study shows that lomefloxacin in a twice daily dose of 400 mg does not effect theophylline metabolism. Lomefloxacin and theophylline can be coadministered without concern about effects of lomefloxacin on theophylline pharmacokinetics.

4-Quinolones↗
PubMed1990

Pharmacokinetics of intravenously administered dantrolene and its 5-hydroxy metabolite in dogs.

Dantrolene, a direct acting muscle relaxant used orally for spasticity, has appeared to be effective in the prevention and treatment of malignant hyperthermia in man and animals when administered intravenously. Its pharmacokinetics following intravenous administration have been studied in dogs. Concentrations of dantrolene and its metabolites in plasma, urine, and bile were determined by high-performance liquid chromatography. Recovery of unchanged drug and reduced metabolites was negligible; of the hydroxy metabolite 2% was found in the urine and about 25% in the bile. The half-life of 5-hydroxydantrolene was shorter than that of the parent drug as demonstrated by administration of the metabolite. The apparent renal clearance of 5-hydroxydantrolene was independent of creatinine clearance, urine flow and pH, and appeared to be reduced in the presence of probenecid. Bile to plasma ratios of the hydroxy metabolite were high with biliary concentrations far exceeding the maximum solubility in water. The results of this pilot study indicate that hydroxylation is primarily responsible for the excretion of the dantrolene molecule from the body.

Animals↗
PubMed1990

Pharmacokinetics of rectal diclofenac and its hydroxy metabolites in man.

Diclofenac 100 mg suppository is well absorbed from the gastrointestinal tract of six human volunteers. Plasma concentrations of 4'-hydroxydiclofenac and diclofenac could be measured; the concentrations of the three other metabolites were below the detection limit of the HPLC analysis. The apparent half-lives of diclofenac and 4'-OH-diclofenac are, respectively 1.3 +/- 0.3 h and 4.3 +/- 1.0 h. When the t 1/2 values are derived from the renal excretion rate-time profiles, they are as follows: diclofenac 1.8 +/- 0.9 h, 3'-OH-, and 5-OH-diclofenac 2.3 +/- 1.0 h and 2.5 +/- 0.4 h, respectively, while those of 4'-OH- and 4',5-diOH-diclofenac are, respectively 3.6 +/- 0.5 h and 3.1 +/- 1.3 h. Diclofenac is excreted for 13.6 +/- 6.5%, its renal clearance (Clr) = 3.23 +/- 1.03 ml/min. The main metabolite excreted in the urine is 4'-OH-diclofenac (27.2 +/- 12% dose; Clr = 6.14 +/- 4.04 ml/min). The total body clearance of the parent drug and the apparent total body clearance of the main metabolite are similar, 28.0 +/- 11.9 l/h and 27.5 +/- 10.9 l/h.

Administration, Rectal↗
PubMed1989

Drug-drug interactions affecting fluoroquinolones.

In a three-week study, the metabolism of the bronchodilator theophylline and its major metabolites formed by C-8 oxidation (1,3-dimethyluric acid) and N-demethylation (3-methylxanthine and 1-methyluric acid) was investigated in two healthy volunteers. Metabolic studies were performed following intravenous infusion of a single 6 mg/kg dose of aminophylline. During Week 1, theophylline was given alone (blank period), and during Weeks 2 and 3 it was given during oral coadministration of ofloxacin and enoxacin, respectively. Dosage of each quinolone was 200 mg twice daily for four days, starting three days prior to the theophylline infusion. During enoxacin coadministration, elimination half-lives of theophylline increased from 8.7 to 17.4 hours and from 6.1 to 12.3 hours, respectively. Total body clearance of theophylline decreased in both volunteers, whereas renal clearance did not alter. From this it was concluded that the decreased elimination results from a reduced metabolic clearance. During enoxacin coadministration, the formation of the metabolites 1-methyluric acid and 3-methylxanthine clearly was decreased, whereas the formation of 1,3-dimethyluric acid was less affected compared with the blank period. Interference with theophylline disposition by enoxacin is based predominantly on inhibition of microsomal N-demethylation. Ofloxacin comedication did not cause a change in the plasma parameters or renal excretion of theophylline and its metabolites compared with the blank period.

Adult↗
PubMed1989

Effect of albumin distribution. A simulation analysis of the effect of altered albumin distribution on the apparent volume of distribution and apparent elimination rate constant of drugs.

The effects of altered albumin distribution on the apparent volume of distribution (V) and the apparent elimination rate constant (kappa) of drugs were investigated by a simulation analysis. The Equations derived by Oie et al. were modified for this purpose. Within the range observed in normal healthy subjects and patients, the change in albumin distribution significantly affected V of drugs but, in general, not kappa. For drugs with more than 90% plasma-protein binding, V changed by more than 100%. The change in plasma-protein binding caused by an altered albumin distribution produced a greater effect on V than that caused by an altered albumin amount. These results suggest that albumin distribution is an important factor in controlling the kinetics of drugs which are highly bound to plasma protein. This is illustrated using midazolam as an example.

Blood Proteins↗
PubMed1989

Plasma and urinary excretion kinetics of oral baclofen in healthy subjects.

Baclofen, a centrally acting muscle relaxant, is used in the treatment of spasticity. Its pharmacokinetics has been derived from plasma and urine data in four healthy subjects, whose renal function was simultaneously measured. After oral administration of a single 40 mg dose, baclofen was mainly excreted unchanged by the kidney, 69 (14)%. The half-life, calculated from extended least squares modelling (ELSMOS) both of plasma and urine data was 6.80 (0.68) h, which is longer than reported in most studies based solely on plasma data. The renal excretion rate constant had the high mean value of 0.35 (0.24) h-1, and the apparent renal clearance of baclofen equalled the creatinine clearance. Passive tubular reabsorption is relatively unimportant, since no dependence was observed on variables urine flow or pH. Although active tubular secretion may contribute to its renal clearance, as shown by the effect of co-administration of probenecid, glomerular filtration appears to be the dominant transport mechanism.

Adult↗
PubMed1989

Decreased plasma albumin concentration results in increased volume of distribution and decreased elimination of midazolam in intensive care patients.

The pharmacokinetic parameters of 16 patients in the intensive care unit, sedated with midazolam, were evaluated. A large variation was observed in the plasma concentration of midazolam and between the plasma concentration of midazolam and its metabolite 1-hydroxymethylmidazolam glucuronide. The plasma albumin concentration governs the volume of distribution of midazolam. Decreased plasma albumin concentration (25 gm/L) results in an increased volume of distribution and a decreased elimination rate of midazolam. The observed plasma concentration ratio between the parent drug and its metabolite 1-hydroxymethylmidazolam glucuronide is governed by the variables of protein binding, the metabolic rate of midazolam, and the renal clearance of the glucuronide metabolite itself (which can be considered as a measure of the kidney function of the patient).

Adult↗
PubMed1989

Excretion and metabolism of a series of xanthines by the turtle Pseudemys scripta elegans.

The xanthines paraxanthine, xanthine, and uric acid are absorbed completely by the turtle Pseudemys scripta elegans and metabolised presumably into CO2 and NH3. No intermediate metabolites are excreted. Caffeine, hydroxycaffein, theobromine, hydroxytheobromine, and hydroxypraxanthine are absorbed and excreted in different amounts or percentages of the dose administered. Intermediate metabolites of these compounds are not excreted. The turtle Pseudemys scripta elegans may, therefore, be ammonotelic.

Animals↗
PubMed1989

Pharmacokinetics and renal clearance of sulphadimidine, sulphamerazine and sulphadiazine and their N4-acetyl and hydroxy metabolites in pigs.

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N4-acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half-lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6-hydroxymethylsulphamerazine and 4-hydroxysulphadiazine were detected in plasma. The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6-hydroxymethyl and 4-hydroxy derivatives) and SDZ (4-hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimination, because their renal clearance values were higher than those of the parent drug.

Animals↗
PubMed1989

Nonlinear pharmacokinetics of intravenous sulphadimethoxine and its dosage regimen in pigs.

The time courses of the total (Ct) and unbound plasma (Cf) concentration after the i.v. injection of 20, 50 and 100 mg/kg of sulphadimethoxine (SDM) were examined in pigs. The area under the Ct-time curve per unit dose decreased dose-dependently. Vdarea and total body clearance of Ct increased dose-dependently. The concentration-dependent plasma protein binding of SDM was evident after 50 and 100 mg/kg. The time courses of Cf en Ct after 3 doses were analyzed by a one compartment open model with nonlinear plasma protein binding. The agreement between calculated curves of Cf and Ct and the observed values, and relative constancy of pharmacokinetic parameters were obtained over 3 doses. These results suggested that the nonlinear pharmacokinetics of SDM was caused by saturable plasma protein binding. The multiple i.v. dose of SDM was based on the dosage regimen using the nonlinear pharmacokinetic model (50 mg/kg, 24 hour interval, 4 days). The observed Cf was maintained in the intended range by the dosage regimen. Therefore, the dosage regimen based on the nonlinear pharmacokinetics may allow the unbound concentration after i.v. injection of SDM in pigs to be controlled.

Animals↗
PubMed1989

Pharmacokinetics and metabolism of sulphadimidine in kids at 12 and 18 weeks of age.

The pharmacokinetics and metabolism of sulphadimidine (SDM) following intravenous administration of 100 mg/kg were studied in seven dwarf preruminant kids at 12 weeks of age, and again at the ruminant stage, when the animals were 18 weeks old. The persistence of SDM in 18-week-old kids was prolonged in comparison to the 12-week-old animals: a lower total body clearance and a prolonged elimination of SDM were obtained in the older animals. The renal clearance values of SDM and its metabolites were the same at both ages. The decrease of SDM clearance is related to the significant reduction in SDM hydroxylation at the older age. The reduced oxidative hepatic metabolism may result from the sexual maturation of the kids.

Age Factors↗
PubMed1989

Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows.

The pharmacokinetic analysis of plasma concentration--time curves after a single i.v. dose of 20 mg/kg sulphatroxazole (STZ) to calves and cows revealed a small distribution volume of STZ (mean VD(area) = 0.22-0.26 l/kg) and an age dependent elimination (mean t1/2 6.6-18.8 h). In calves and cows, STZ was extensively metabolized into the N4-acetyl and 5-hydroxy derivatives. In the plasma of calves, the N4-acetyl metabolite (N4-STZ) was present in greater amounts than the hydroxy metabolite (5-OH-STZ), while in cows' plasma concentration of these two metabolites were similar. In the milk of dairy cows STZ concentrations paralleled those of the metabolites and were approximately 21 times lower than corresponding plasma concentrations. The mean plasma protein binding of STZ and its metabolites ranged from 36.4 to 82.5% of total concentration. The N4-STZ derivative was excreted by tubular secretion; the 5-OH-STZ and the parent compound, mainly by glomerular filtration. In calves the majority of STZ administered was excreted as N4-STZ (40-52%), while in cows the parent drug dominated the urinary excretion (36%).

Acetylation↗