Biomedical subjects
Publications and source records attributed to T B Vree.
Sulpha-2-monomethoxine is N4-acetylated to an extent of 12% of the dose by Pseudemys scripta elegans; 48% is excreted unchanged. No O-dealkylation of the 2-methoxy group takes place.
The sulphonamides sulphapyridine and sulphadiazine show novel hydroxy metabolites in the turtle Pseudemys scripta elegans. In the excreta of the turtles the monohydroxy metabolites 4-hydroxy- and 5-hydroxysulphapyridine and the dihydroxy metabolite 4,5-dihydroxysulphapyridine were detected. Of sulphadiazine only dihydroxy metabolites 4,5- and 4,6-dihydroxysulphadiazine were detected. About 70-90% of the dose of sulphapyridine was recovered, while this figure varied between 48 and 69% for sulphadiazine.
Pigs are unable to form N1-glucuronides of sulphadimethoxine and sulphamethomidine, while humans are able to do so. Pigs and humans are able to oxidise sulphapyridine and form the O-glucuronide. The double conjugate N4-acetylsulphapyridine-O-glucuronide is formed in humans but not in pigs. Sulphadiazine is mainly acetylated in both humans and pigs. A hypothesis about N1-glucuronidation is presented.
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This study investigated the pharmacokinetics of midazolam and its main metabolite, 1-hydroxymethylmidazolam glucoronide, during long-term i.v. infusion in 39 mechanically ventilated ICU patients of whom 6 were in acute renal failure (ARF). The mean infusion rate of midazolam was similar (9.4 vs 8.7 mg/h) in the control patients and those with ARF. The renal clearance of 1-hydroxymethylmidazolam glucuronide was much lower in the ARF group than in the control group (3.9 vs 136 ml/min). Consequently, its plasma elimination half-life after discontinuation was also greatly prolonged, but this shouldn't cause very prolonged sedative effects since this metabolite is much less active than the parent drug. However, the half-life of midazolam itself was also significantly longer in patients with ARF than in the control group (13.2 vs 7.6 h). Apparently, this was caused by a combination of a slightly lower total clearance and a higher volume of distribution. Therefore, regular reassessment of the degree of sedation and appropriate adaptation of the infusion rate of midazolam are recommended in ICU patients with ARF.
A direct high pressure liquid chromatographic analysis of sulfaphenazole-N2-glucuronide in urine is described. After an oral dose of 439 mg of sulfaphenazole, 0% is excreted unchanged in the urine, less than 1% is excreted as N4-acetylsulfaphenazole. As N2-glucuronide 49.4% is excreted in one slow acetylator and 84.8% in one fast acetylator.
Cefuroxime is well-absorbed and distributed over the human body. This review gives a general summary of published information on tissue concentrations of cefuroxime after an intravenous or intramuscular dose of 750 or 1,500 mg of cefuroxime. Tissue concentrations are given for blister fluid, meninges, eyes, respiratory tract, sputum and bronchi, abdominal and urogenital tract, uterine, ovarian and fallopian tube tissue, myometrium, membranes, placenta, puruloid and healthy human milk, bile, prostate, hip and knee bone. Pharmacokinetics are reviewed in patients with impaired kidney function and in pregnancy.
To 6 pregnant patients with preterm premature rupture of the membranes, cefuroxime prophylaxis was given 1,500 mg three times daily intravenously. Cefuroxime concentrations were assayed in maternal plasma and amniotic fluid during pregnancy and in umbilical cord blood, placenta, and membranes after delivery. Our results showed a high rate of transplacental transfer of cefuroxime. Bactericidal levels could be demonstrated in maternal plasma, and in amniotic fluid leaking from the vagina. Therapeutically active levels were present in the newborns. The absorption of cefuroxime by the foetal membranes was high. Although the neonatal morbidity in this high-risk population was low, the data are still too preliminary to advise the routine prophylactic use of cefuroxime to pregnant patients with preterm premature rupture of the membranes.
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The bioavailability of two prazosin formulations was studied in 12 healthy volunteers. 1 Subject left the study. Based on the statistical tests of the pharmacokinetic parameters of prazosin in 11 volunteers, such as t 1/2, Cmax, tmax and AUC, it could be concluded that both preparations had comparable bioavailabilities.
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Sulfadimethoxine is metabolized by O-dealkylation, N4-acetylation and N1-glucuronidation. In man, only N1-glucuronidation and N4-acetylation takes place, leading to the final double conjugate N4-acetylsulfadimethoxine-N1-glucuronide. The N1-glucuronides are directly measured by high pressure liquid chromatography. When N4-acetylsulfadimethoxine is administered as parent drug, 30% of the dose is N1-glucuronidated and excreted. Fast acetylators show a shorter half-life for sulfadimethoxine than slow acetylators (27.8 +/- 4.2 h versus 36.3 +/- 5.4 h; P = 0.013), similarly the half-life of the N4-acetyl conjugate is also shorter in fast acetylators (41.3 +/- 5.2 h versus 53.5 +/- 8.5 h, P = 0.036). No measurable plasma concentrations of the N1-glucuronides from sulfadimethoxine are found in plasma. N1-glucuronidation results in a 75% decrease in protein binding of sulfadimethoxine. N4-acetylsulfadimethoxine and its N1-glucuronide showed the same high protein binding of 99%. Approximately 50-60% of the oral dose of sulfadimethoxine is excreted in the urine, leaving 40-50% for excretion into bile and faeces.
The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30-80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (+/- 0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml.min-1 (+/- 44), plasma protein binding 35% (+/- 6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (+/- 16). Its apparent renal equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.
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Sulphadimethoxine is metabolized in humans by N1-glucuronidation and by N4-acetylation. Sulphadimethoxine-N1-glucuronide can be measured by the direct high-performance liquid chromatographic analysis and without enzymic deglucuronidation. The N1-glucuronide can be measured by an isocratic as well as by a gradient mobile phase. The group contribution of the N1-glucuronide moiety to the capacity factor is a reduction of 0.24 in the isocratic system and 0.55 in the gradient system. N4-Acetylation increases the capacity factor by a factor 1.4 in the isocratic system and by 1.06 in the gradient system.
N-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 beta was 0.2 hours (12 minutes) and t1/2 tau was 0.75 +/- 0.1 hours (45 +/- 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 tau was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.
Differences in pharmacokinetic data of aminoglycosides, ceftazidime and ceftriaxone between intensive care patients and volunteers or patients who are less severely ill, are described. Similar differences are observed for midazolam. In severely ill patients with normal renal function a wide interpatient variability of aminoglycoside half-life (t1/2) and increased distribution volume (Vd) are observed. This results in inadequate serum levels. A pharmacokinetic approach of drug dosing, based on serum concentrations in individual patients, is advised. For ceftazidime and ceftriaxone similar changes of t1/2 and Vd are observed. Since protein binding is frequently reduced in severely ill patients, the influence of altered binding of highly bound drugs on Vd and drug clearance is discussed. As both may be increased by reduced protein binding, the change of t1/2 to be expected is unpredictable. Dosing regimens should be based on pharmacokinetic data derived from patients whose severity of disease is comparable to that of the patients to be treated.