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T B Vree

Publications and source records attributed to T B Vree.

At least 19 recordsLinked to original sources
PubMed1992

Capacity-limited renal glucuronidation of probenecid by humans. A pilot Vmax-finding study.

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, the t1/2 increased from 3 to 6 h. The Cmax was 14 micrograms/ml with a dosage of 250 mg, 31 micrograms/ml with 500 mg, 70 micrograms/ml with 1,000 mg and 120 micrograms/ml with 1,500 mg. The tmax remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6-0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34-59%). The protein binding of probenecid glucuronide in vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate--time profile of probenecid glucuronide shows a plateau value of approximately 700 micrograms/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects its Vmax of formation.

Adult↗
PubMed1992

Direct-gradient high-performance liquid chromatographic analysis and preliminary pharmacokinetics of flumequine and flumequine acyl glucuronide in humans: effect of probenecid.

A gradient high-performance liquid chromatographic analysis for the direct measurement of flumequine, with its acyl glucuronide, in plasma and urine of humans has been developed. In order to prevent hydrolysis and isomerization of flumequine acyl glucuronide, the samples were acidified by the oral intake of four 1.2-g amounts of ammonium chloride per day. In contrast to the acyl glucuronides of non-steroidal anti-inflammatory drugs, flumequine and its acyl glucuronide were stable in urine of pH 5.0-8.0. Flumequine acyl glucuronide is unstable at pH 1.5. In acidic urine (pH 5-6), almost no flumequine is excreted unchanged (1%): it is excreted chiefly as acyl glucuronide (84.2%). Probenecid co-medication reduces the renal excretion rate of flumequine acyl glucuronide from 662 to 447 micrograms/min (p = 0.00080), but not the percentage of glucuronidation.

Anti-Infective Agents↗
PubMed1992

Determination of naproxen and its metabolite O-desmethylnaproxen with their acyl glucuronides in human plasma and urine by means of direct gradient high-performance liquid chromatography.

Naproxen is metabolized in humans by O-demethylation, and by acyl glucuronidation to the 1-O-glucuronide. Naproxen, its metabolite and the conjugates can be measured directly by gradient high-performance liquid chromatographic analysis without enzymic deglucuronidation. The glucuronide conjugates were isolated by preparative chromatography from human urine samples. Mild acidic hydrolysis of one urinary conjugate resulted in naproxen. This conjugate was also formed by alkaline isomerization of isolated naproxen acyl glucuronide, indicating that the structure of this urinary conjugate must have been naproxen isoglucuronide (4-O-glucuronide). Mild acidic hydrolysis of another urinary conjugate resulted in O-desmethylnaproxen. This conjugate was also formed by alkaline isomerisation of isolated O-desmethylnaproxen acyl glucuronide, indicating that the structure of this urinary conjugate must have been O-desmethylnaproxen isoglucuronide (4-O-glucuronide). Calibriation curves were constructed by enzymic deconjugation of samples containing different concentrations of isolated naproxen acyl glucuronide, O-desmethylnaproxen acyl glucuronide, and the isoglucuronides of naproxen and O-desmethylnaproxen by mild acidic hydrolysis. The limit of quantitation of naproxen in plasma is 1.5 microgram/ml. The limits of quantitation in urine are: naproxen, O-desmethylnaproxen, naproxen acyl glucuronide and O-desmethylnaproxen acyl glucuronide, 1 microgram/ml; the isoglucuronide of naproxen and O-desmethylnaproxen, 1.5 microgram/ml. A pharmacokinetic profile of naproxen is shown, and some preliminary pharmacokinetic parameters of naproxen obtained from two human volunteers are given.

Acylation↗
PubMed1992

Direct measurement of probenecid and its glucuronide conjugate by means of high pressure liquid chromatography in plasma and urine of humans.

Probenecid with its phase-I metabolites, and phase-II glucuronide conjugate can be analysed by a gradient high pressure liquid chromatographic method. Probenecid glucuronide in plasma with pH 7.4 is not stable and declines to 10% of the original value within 6 h (t1/2 approximately 1 h). Probenecid glucuronide is stable in urine with pH 5.0, moderately unstable at pH 6.0 (t1/2 approximately 10 h), and unstable at pH 8.0 (t1/2 approximately 0.5 h). Probenecid glucuronide is stable in water and 0.01 mol/l phosphoric acid in the autosampler of the high pressure liquid chromatograph. The decrease in concentration in water is 5.5% during 9 h and 0% in diluted acid. Probenecid glucuronide and the phase-I metabolites were not detectable in plasma. The main compound in fresh urine is the phase-II conjugate probenecid glucuronide (62% of a 500 mg dose); the phase-I metabolites are present and only a trace of probenecid is present. The percentage of the dose of the phase-I metabolites varies between 5 and 10, while hardly any probenecid is excreted unchanged (0.33%).

Chromatography, High Pressure Liquid↗
PubMed1992

High-performance liquid chromatography and preliminary pharmacokinetics of rufloxacin and its metabolites, N-desmethylrufloxacin and rufloxacinsulfoxide, in urine of rhesus monkey Macaca mulatta.

A gradient high-performance liquid chromatographic method for the quantification of rufloxacin and two of its metabolites in urine, N-desmethylrufloxacin and rufloxacinsulfoxide, has been developed and validated. Monkey urine samples were diluted ten times with distilled water and 20 microliters were injected onto a Cp Spher 5-ODS column, 5 microns particle size. The mobile phase was a mixture of 4% acetonitrile and 96% buffer at time 0, which changed linearly over 37 min to 26% acetonitrile and 74% buffer. Detection was achieved at 246 nm. The limit of detection of the three compounds was 0.50 microgram/ml. An example of a pharmacokinetic study of rufloxacin and its metabolites in monkeys is shown.

Animals↗
PubMed1992

Pharmacokinetics and acetylation of sulfa-2-monomethoxine in humans.

In humans sulfa-2-monomethoxine (S) is metabolized by N4-acetylation (39.9 +/- 8.0 per cent). After an oral dose, S is eliminated biphasically (t1/2, 5.2 +/- 1.6 h and 13.2 +/- 3.4 h) which is similar in both fast and slow acetylators. The metabolite N4-acetylsulfa-2-monomethoxine (N4) is eliminated monophasically (t1/2, 30.0 +/- 5.7 h). The intrinsic mean residence time (MRT) of N4 is 33.5 +/- 8.8 h. The mean total body clearance of S is 11.6 +/- 2.7 ml min-1, and the Vdss is 12.3 +/- 1.01. The renal clearance of S during the first day was twice as high as on the following days for two of the six volunteers (8 vs 4 ml min-1). The renal clearance of N4 during the first day, for four out of the six volunteers, was twice as high as on the following days (8 vs 4 ml min-1). The protein binding of S is 95 per cent and that of its conjugate N4 98 per cent. Approximately 80 per cent of the oral dose of S is excreted in the urine as parent drug (41.0 +/- 6.2 per cent) and as N4 acetyl conjugate (39.9 +/- 8.0 per cent).

Acetylation↗
PubMed1992

Pharmacokinetics and metabolism of codeine in humans.

Codeine (30 mg phosphate) was metabolized by eight human volunteers to the following six metabolites: codeine-6-glucuronide 81.0 +/- 9.3 per cent, norcodeine 2.16 +/- 1.44 per cent, morphine 0.56 +/- 0.39 per cent, morphine-3-glucuronide 2.10 +/- 1.24 per cent, morphine-6-glucuronide 0.80 +/- 0.63 per cent, and normorphine 2.44 +/- 2.42 per cent. Two out of eight volunteers were unable to O-dealkylate codeine into morphine and lack therefore the cytochrome P450 IID6 isoenzyme. The half-life of codeine was 1.47 +/- 0.32 h, that of codeine-6-glucuronide 2.75 +/- 0.79 h, and that of morphine-3-glucuronide 1.71 +/- 0.51 h. The systemic clearance of codeine was 2280 +/- 840 ml min-1, the renal clearance of codeine was 93.8 +/- 29.8 ml min-1, and that of codeine-6-glucuronide was 122 +/- 39.2 ml min-1. The plasma AUC of codeine-6-glucuronide is approximately 10 times higher than that of codeine. Protein binding of codeine and codeine-6-glucuronide in vivo was 56.1 +/- 2.5 per cent and 34.0 +/- 3.6 per cent, respectively. The in vitro protein binding of norcodeine was 23.5 +/- 2.9 per cent; of morphine, 46.5 +/- 2.4 per cent; of normorphine, 23.5 +/- 3.5 per cent; of morphine-3-glucuronide, 27.0 +/- 0.8 per cent; and of morphine-6-glucuronide, 36.7 +/- 3.8 per cent.

Adult↗
PubMed1992

Bioavailability of lithium from lithium citrate syrup versus conventional lithium carbonate tablets.

The bioavailability of lithium citrate syrup was compared with that of regular lithium carbonate tablets in 18 healthy male human volunteers. Blood samples were collected up to 48 h after dosing. Lithium serum concentrations were determined by means of AAS. The absorption rate following oral administration of the syrup was greater (tmax 0.8 h) than following administration of regular tablets (tmax 1.4 h). Maximum lithium serum concentrations, however, were only about 10 per cent higher after syrup dosing and serum concentrations resulting from syrup and tablets were almost superimposable from 2 h after dosing. The terminal half-life of lithium was found to be 22 h after syrup as well as after tablet dosing. No side-effects were observed during the study. The bioavailability of lithium from syrup relative to tablets was found to be bioequivalent with respect to the maximum lithium serum concentration and the extent of drug absorption (AUC).

Administration, Oral↗
PubMed1992

Pharmacokinetic analysis of ester prodrugs of valproic acid.

The pharmacokinetics of five monoester prodrugs of valproic acid (VPA) were investigated: propyl valproate (P-VPA), butyl valproate (B-VPA), isobutyl valproate (IB-VPA), isoamyl valproate (IA-VPA), and hexyl valproate (H-VPA). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPA and valpromide (VPD). The pharmacokinetics of VPA and its five ester derivatives were determined after intravenous administration of equivalent doses (400 mg of VPA) to six dogs. The five ester prodrugs of VPA were biotransformed to VPA; the biotransformation was complete for P-VPA, B-VPA, and H-VPA but was only partial for IB-VPA and IA-VPA. Because of the rapid conversion of the prodrugs to the parent drug, levels of VPA in plasma after administration of the prodrugs peaked at 6-26 min after dosing and did not yield an in vivo sustained-release dosage profile. Of the five ester prodrugs of VPA, only P-VPA demonstrated anticonvulsant activity. P-VPA also was less neurotoxic than VPA and VPD; therefore, it has a better protective index.

Animals↗
PubMed1992

Contribution of the human kidney to the metabolic clearance of drugs.

OBJECTIVE: To demonstrate that the human kidney is capable not only of filtering and secreting drugs and their metabolites, but also of carrying out conjugation reactions such as acyl glucuronidation, N-glucuronidation, and glycination. DATA SOURCES: Plasma concentrations and renal excretion rates of drugs are measured and renal clearance is calculated in a series of selected pharmacokinetic studies in healthy human volunteers (some studies were conducted in the authors' laboratory and others were reported in the literature). BACKGROUND THEORY: It is generally agreed that the liver plays the dominant role in drug metabolism, and that the function of the kidneys is limited to excretion of parent drug and metabolites. This can be easily understood when a metabolite is present in both plasma and urine. When the metabolite is present in urine but is not measurable in plasma, then the possibility exists that the metabolite is formed by the kidneys. RESULTS: "Simple" excretion by the kidneys is demonstrated for sulfatroxazole/sulfamethoxazole. Ether glucuronides of codeine are formed in the liver, and the resulting glucuronide is excreted by the kidneys. Possible formation of N1- and N2-glucuronides by the kidneys is demonstrated for sulfadimethoxine, sulfametomidine, and sulfaphenazole. Acyl glucuronidation of probenecid and nalidixic acid is carried out by the kidneys. The acyl glucuronidation of probenecid shows a capacity-limited formation/excretion rate of 46 mg/h, which is subject dependent. During this process, the acyl glucuronidation of co-administered nalidixic acid is reduced from 53 to 16 percent compared with that of nalidixic acid alone. Probenecid and its acyl glucuronidation do not inhibit the ether glucuronidation of codeine in the liver, but only interfere with the active tubular secretion process. The acyl glucuronidation of the nonsteroidal antiinflammatory drug naproxen and its metabolite, O-desmethylnaproxen, may be carried out by the liver and kidneys. Glycination of benzoic acid and salicylic acid is carried out in both the liver and kidneys. CONCLUSIONS: It is difficult to recognize renal drug metabolism in the intact human body (in vivo); the glucuronides or conjugates must be measured via direct HPLC analysis. In cases where the metabolite is present in high concentrations in urine but not in blood, there may be an indication that the kidneys are responsible for the formation of the metabolite. Impaired kidney function not only affects renal excretion but may also affect renal metabolism.

Glucuronates↗
PubMed1992

Clinical pharmacokinetics of R(+)- and S(-)-mepivacaine after high doses of racemic mepivacaine with epinephrine in the combined psoas compartment/sciatic nerve block.

The purpose of this study was to investigate the pharmacokinetics of R(+)- and S(-)-mepivacaine in 10 male patients after injection of a high dose (731 mg) of racemic R,S-mepivacaine for a combined psoas compartment/sciatic nerve block. Arterial blood samples were taken, and the plasma concentrations of the stereoisomers R(+)- and S(-)-mepivacaine were measured by means of high-performance liquid chromatography (HPLC) with a Chiral AGP column. The S(-) isomer reached higher plasma concentrations than the R(+) isomer. The maximal plasma concentration (Cmax) of R(+) was 1.54 +/- 0.34 micrograms/mL, whereas that of the S(-) isomer was 2.34 +/- 0.51 micrograms/mL (P = 0.00050). The time at which Cmax was reached (Tmax) was identical for both isomers. The area under the plasma concentration-time curve from t = 0 to infinity (AUC infinity) of S(-)-mepivacaine was almost double that of R(+)-mepivacaine. The elimination half-life (T1/2) was identical for both isomers (3 h), which means that the calculated total body clearance and the calculated steady-state volume of the distribution of R(+) are, respectively, 1.7 and 1.5 times larger than that of the S(-) isomer. We conclude that the plasma concentrations of the S(-)-mepivacaine isomer were higher than those of the R(+) isomer because of a smaller volume of distribution and a slower total body clearance.

Adult↗
PubMed1991

Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfamethomidine in humans.

Sulfamethomidine metabolism was studied in 6 volunteers. In humans, only N1-glucuronidation and N4-acetylation take place, leading to the final double conjugate N4-acetylsulfamethomidine N1-glucuronide. The N1-glucuronides were directly measured by high pressure liquid chromatography. Fast and slow acetylators show a similar half-life for sulfamethomidine (26 +/- 6 h) and its conjugates sulfamethomidine (26 +/- 6 h) and N4-acetylsulfamethomidine (36 +/- 16 h). Approximately 50-60% of the oral dose of sulfamethomidine is excreted in the urine, leaving 40-50% for excretion into bile and faeces. The main metabolite of sulfamethomidine is its N1-glucuronide, which accounts for 36 +/- 7% of the dose, followed by N4-acetylsulfamethomidine (16 +/- 8%). N1-glucuronidation results in a 75% decrease in protein binding of sulfamethomidine. N4-acetylsulfamethomidine and its N1-glucuronide showed the same high protein binding of 99%. The renal clearance of N4-acetylsulfamethomidine is 7.9 +/- 2.2 ml/min and approximately 20 times as high as that of the parent drug (0.46 +/- 0.16 ml/min). Total body clearance of sulfamethomidine is 4.5 +/- 0.9 ml/min and the volume of distribution in steady state 10.6 +/- 1.7 1. No measurable plasma concentrations of the N1-glucuronides from sulfamethomidine are found in plasma. This may be explained by renal glucuronidation after active tubular reabsorption.

Acetylation↗
PubMed1991

Direct determination of codeine, norcodeine, morphine and normorphine with their corresponding O-glucuronide conjugates by high-performance liquid chromatography with electrochemical detection.

A high-performance liquid chromatographic method has been developed for the detection, separation and measurement of codeine and its metabolites norcodeine, morphine and normorphine, with their glucuronide conjugates. The glucuronidase Escherichia coli type VIIA hydrolyses codeine-6-glucuronide completely and is used for the construction of the calibration curves of codeine-6-glucuronide. Enzymic hydrolysis of codeine-6-glucuronide depends on the specific activity of the glucuronidase applied. Examples are shown of a volunteer who is able to form morphine from codeine and one who is unable to do so.

Chromatography, High Pressure Liquid↗
PubMed1991

Rapid determination of succinylcholine in human plasma by high-performance liquid chromatography with fluorescence detection.

A high-performance liquid chromatographic method with fluorometric detection has been developed for the determination of succinylcholine in human plasma. Succinylcholine shows fluorescence at 282 nm with an excitation at 257 nm. The assay is sensitive, reproducible and linear for concentrations ranging from 100 ng/ml to 100 micrograms/ml of succinylcholine. In a pilot study the plasma concentration-time curve showed a triphasic elimination, with half-lives of 0.4, 1.2 and 8 min, respectively. In a clinical setting, drugs commonly administered during anaesthesia did not interfere with the assay. This method provides a simple and time-saving alternative to existing methods.

Chromatography, High Pressure Liquid↗
PubMed1991

Adverse reactions to co-trimoxazole in HIV infection.

The origin of the increased frequency of side-effects to co-trimoxazole in HIV-positive patients is unknown. Data on plasma concentrations of the parent compounds are inconclusive. Evidence points to the hydroxylamine derivatives of sulphamethoxazole as the reactive metabolites that cause adverse reactions to co-trimoxazole. HIV-positive individuals have a systemic glutathione deficiency, and therefore a reduced capacity to scavenge such metabolites. This process would lead to an increased exposure to toxic intermediates and would explain the high frequency of adverse reactions to co-trimoxazole in these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Pharmacokinetics of nicomorphine and its metabolites in man after epidural administration.

In ten patients who received an epidural injection of 15 mg of nicomorphine, the compound was relatively slowly released from the epidural space and was found in plasma for approximately 1.5 h. Nicomorphine is relatively slowly metabolized into 6-nicotinoylmorphine and morphine. The rate of release is patient-dependent. The relative AUC values are 15.3% for nicomorphine, 23.9% for 6-nicotinoylmorphine and 60.8% for morphine. The mean clinical effect lasts for 18.2 +/- 10.1 h.

Adolescent↗
PubMed1991

Direct high pressure liquid chromatographic analysis and preliminary pharmacokinetics of enantiomers of oxazepam and temazepam with their corresponding glucuronide conjugates.

Three high pressure liquid chromatographic systems for the separation of oxazepam, temazepam and their glucuronides (system A), the separation of their R,S glucuronide diastereomers (system B) and the chiral separation of the parent drugs (system C) are described. Preliminary pharmacokinetics of R,S-oxazepam and R,S-temazepam in a human volunteer reveal that the protein binding of the glucuronides is lower than that of the parent drugs, but that there is no difference in protein binding between the R-oxazepam/temazepam and S-oxazepam/temazepam and their corresponding glucuronides. The S-glucuronide is the main metabolite formed and excreted by man. The plasma ratio R/S-glucuronide is 1:1 for both oxazepam and temazepam. The renal clearance of R-temazepam, and S-temazepam are similar, and those of R-oxazepam and S-oxazepam tend to be different.

Chromatography, High Pressure Liquid↗