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Biomedical subjects

T B Vree

Publications and source records attributed to T B Vree.

At least 55 records · Page 3Linked to original sources
PubMed1995

Comparison of the bioavailability and pharmacokinetics of oral methylergometrine in men and women.

OBJECTIVE: To assess and compare the pharmacokinetics and bioavailability of methylergometrine (ME) in men and non-pregnant women. DESIGN: A cross-over design was used for an oral dose of 0.125 mg and an intravenous dose of 0.200 mg of ME in 6 men and 6 non-pregnant women (parallel-design in gender). RESULTS: After intravenous administration, the pharmacokinetic profile of ME was described with a 2-compartment model. The distribution half-life (t1/2 alpha) in men was 0.19 +/- 0.27 h, in women 0.10 +/- 0.04 h, the elimination half-life (t1/2 beta) 1.85 +/- 0.28 h, respectively, 1.94 +/- 0.34 h and the total body clearance (CL) 33.2 +/- 11.8 l.h-1, and, respectively, 22.18 +/- 3.10 l.h-1. For these intrinsic pharmacokinetic parameters differences between men and women were not statistically significant. After oral administration, the pharmacokinetic profile was described with a 1-compartment model. The lag time was subject dependent and was significantly longer in men 0.33 +/- 0.09 h than in women 0.09 +/- 0.07 h. T1/2 beta in men was 2.08 +/- 0.43 h and was longer than in women 1.42 +/- 0.31 h (p = 0.012). In both men and women a large variation of bioavailability was shown ranging between 22% and 138%. CONCLUSION: This study with oral methylergometrine showed a comparable large interindividual variability in bioavailability in both men and women.

Administration, Oral↗
PubMed1995

Probenecid inhibits the renal clearance of frusemide and its acyl glucuronide.

The effect of oral probenecid (1 g) on the pharmacokinetics of frusemide (80 mg p.o.) and its acyl glucuronide was studied in nine healthy subjects. Probenecid significantly increased the t1/2,z of frusemide from 2.01 +/- 0.68 to 3.40 +/- 1.48 h (P = 0.0015) and significantly decreased oral clearance from 164 +/- 67.0 to 58.3 +/- 28.1 ml min-1 (P = 0.0001). No effect of probenecid on the plasma protein binding of frusemide was detected. Probenecid significantly increased the tmax of the metabolite frusemide acyl glucuronide from 1.4 to 2.6 h, but had no effect on the tlag, Cmax, t1/2,z and plasma protein binding. The urinary recoveries of unchanged frusemide (39.2 +/- 10.2 vs 34.4 +/- 8.6%, P = 0.28) and its acyl glucuronide (12.1 +/- 2.7 vs 11.8 +/- 3.7%, P > 0.8) were not altered by probenecid. However, probenecid decreased the renal clearance of both frusemide (128 +/- 49 vs 44.0 +/- 18.6 ml min-1, P = 0.0002) and the acyl glucuronide (552 +/- 298 vs 158 +/- 94.0 ml min-1, P < 0.0001). The non-renal clearance of frusemide (36.7 +/- 21.0 vs 15.2 +/- 13.4 ml min-1, P = 0.0068) was also decreased. The clinical relevance of the study relates to the possible conjugation of frusemide in the kidney and the role of the conjugate in the pharmacodynamic effect.

Adult↗
PubMed1995

The bioavailability of intramuscularly administered nicomorphine (Vilan) with its metabolites and their glucuronide conjugates in surgical patients.

The kinetics of 20 mg nicomorphine intramuscularly were described in 8 patients under combined general and epidural anesthesia. The half-life of nicomorphine was 0.32 +/- 0.20 h (mean +/- SD) and is governed by the absorption-rather than the elimination rate. The half-life of 6-mononicotinoylmorphine (0.39 +/- 0.09 h) was identical to that of the parent compound (p = 0.29), suggesting it is directly related to the absorption rate of nicomorphine. Morphine had a half-life of 1.38 +/- 0.31 h. Morphine is subsequently metabolized into morphine-3-glucuronide and morphine-6-glucuronide. The half-life of these 2 glucuronide conjugates was about 2.6 h (p = 0.07). A glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In urine only morphine and its glucuronides are found, with renal clearance values of 214 ml.min-1 for morphine and 132 ml.min-1 for the glucuronides. The bioavailability of this pharmaceutical formulation after intramuscular administration equals that of intravenous administration in surgical patients (at the same dose).

Adult↗
PubMed1994

Rectal administration of nicomorphine in patients improves biological availability of morphine and its glucuronide conjugates.

The pharmacokinetics of 30 mg nicomorphine after rectal administration with a suppository are described in 8 patients under combined general and epidural anaesthesia. No nicomorphine or 6-mononicotinoylmorphine could be detected in the serum. Morphine appeared almost instantaneously with a lag-time of 8 min and had a final elimination half-life of 1.48 +/- 0.48 h. Morphine was metabolized to morphine-3-glucuronide and morphine-6-glucuronide. These glucuronide conjugates appeared after a lag-time of 12 min and the half-life of these two glucuronide conjugates was similar: about 2.8 h (P > 0.8). The glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In the urine only morphine and its glucuronides were found. The renal clearance value for morphine was 162 ml.min-1 and for the glucuronides 81 ml.min-1. This study shows that administration of a suppository with 30 mg nicomorphine gives an excellent absolute bioavailability of morphine and its metabolites of 88%. The lipid-soluble prodrug nicomorphine is quickly absorbed and immediately hydrolysed to morphine.

Administration, Rectal↗
PubMed1994

Isolation, identification and determination of sulfamethoxazole and its known metabolites in human plasma and urine by high-performance liquid chromatography.

From human urine the following metabolites of sulfamethoxazole (S) were isolated by preparative HPLC: 5-methylhydroxysulfamethoxazole (SOH), N4-acetyl-5-methylhydroxysulfamethoxazole (N4SOH) and sulfamethoxazole-N1-glucuronide (Sgluc). The compounds were identified by NMR, mass spectrometry, infrared spectrometry, hydrolysis by beta-glucuronidase and ratio of capacity factors. The analysis of S and the metabolites N4-acetylsulfamethoxazole (N4), SOH, N4-hydroxysulfamethoxazole (N4OH), N4SOH, and Sgluc in human plasma and urine samples was performed with reversed-phase gradient HPLC with UV detection. In plasma, S and N4 could be detected in high concentrations, while the other metabolites were present in only minute concentrations. In urine, S and the metabolites and conjugates were present. The quantitation limit of the compounds in plasma are respectively: S and N4 0.10 micrograms/ml; N4SOH 0.13 micrograms/ml; N4OH 0.18 micrograms/ml; SOH 0.20 micrograms/ml; and Sgluc 0.39 microgram/ml. In urine the quantitation limits are: N4 and N4OH 1.4 micrograms/ml; S 1.5 micrograms/ml; N4SOH 1.9 micrograms/ml; SOH 3.5 micrograms/ml; and Sgluc 4.1 micrograms/ml. The method was applied to studies with healthy subjects and HIV positive patients.

Adult↗
PubMed1994

Determination of furosemide with its acyl glucuronide in human plasma and urine by means of direct gradient high-performance liquid chromatographic analysis with fluorescence detection. Preliminary pharmacokinetics and effect of probenecid.

Furosemide is metabolized in humans by acyl glucuronidation to the 1-O-glucuronide (Fgluc). Furosemide (F) and the conjugate can be measured directly by gradient high-performance liquid chromatographic analysis without enzymic deglucuronidation. The glucuronide conjugate was isolated by preparative HPLC from human urine samples. Furosemide and its acyl glucuronide were present in plasma. No isoglucuronides were present in acidic urine of a volunteer. Calibration curves were constructed by enzymic deconjugation of samples containing different concentrations of isolated F-acyl glucuronide. The limit of quantitation of F in plasma is 0.007 microgram/ml, Fgluc 0.010 microgram/ml. The limits of quantitation in urine are respectively: F 0.10 microgram/ml, Fgluc 0.15 microgram/ml. A pharmacokinetic profile of furosemide is shown, and some preliminary pharmacokinetic parameters of furosemide obtained from one human volunteer are given. Probenecid does not inhibit the formation of the acyl glucuronide of F, but inhibits the renal clearance of both compounds.

Chromatography, High Pressure Liquid↗
PubMed1994

Probenecid inhibits the glucuronidation of indomethacin and O-desmethylindomethacin in humans. A pilot experiment.

Indomethacin is metabolized in humans by O-demethylation, and by acyl glucuronidation to the 1-O-glucuronide. Indomethacin, its metabolite, and their conjugates can be measured directly by gradient high-pressure liquid chromatographic analysis without enzymic deglucuronidation. The pharmacokinetic profile of indomethacin and some preliminary pharmacokinetic parameters of indomethacin obtained from one human volunteer are given. In plasma only the parent drug indomethacin is present, while in urine the acyl and ether glucuronides are present in high concentrations. This confirms other reports that indomethacin and O-desmethylindomethacin may be glucuronidated in the kidney. Probenecid is a known substrate for renal glucuronidation. If indomethacin is glucuronidated in the human kidney like probenecid, then this glucuronidation might be reduced or inhibited under probenecid co-medication. This pilot experiment shows that probenecid reduced the acyl glucuronidation of indomethacin by 50% and completely inhibited the formation of O-desmethylindomethacin acyl and ether glucuronide.

Chromatography, High Pressure Liquid↗
PubMed1994

Direct gradient reversed-phase high-performance liquid chromatographic determination of salicylic acid, with the corresponding glycine and glucuronide conjugates in human plasma and urine.

A gradient reversed-phase HPLC analysis for the direct measurement of salicylic acid (SA) with the corresponding glycine and glucuronide conjugates in plasma and urine of humans was developed. The glucuronides were isolated by preparative HPLC from human urine samples. The concentration of the glucuronides in the isolated fraction were determined after enzymatic hydrolysis. Salicylic acid acyl glucuronide (SAAG) was not present in plasma. No isoglucuronides were present in acidic and alkaline urine of the volunteer. The limits of quantitation in plasma are: SA 0.2 microgram/ml, salicyluric acid (SU) 0.1 microgram/ml, salicylic acid phenolic glucuronide (SAPG) 0.4 microgram/ml and salicyluric acid phenolic glucuronide (SUPG) 0.2 microgram/ml. The limit of quantitation in urine is for all compounds 5 micrograms/ml. Salicylic acid acyl glucuronide is stable in phosphate buffer pH 4.9 during 8 h at 37 degrees C; thereafter it declines to 80% after 24 h. The subject's urine was therefore acidified by the oral intake of 4 x 1.2 g of ammonium chloride/day. With acidic urine, hardly any salicylic acid is excreted unchanged (0.6%). It is predominantly excreted as salicyluric acid (68.7%).

Acylation↗
PubMed1994

Pharmacokinetics and bioavailability of oral ergometrine in male volunteers.

The aim of this investigation was to assess the pharmacokinetics and bioavailability of ergometrine in six human male subjects after an oral dose of 0.200 mg and after an intravenous dose of 0.075 mg of ergometrine maleate. A large variation in bioavailability of between 34% and 117% in the six volunteers was observed. The lag time was also subject dependent and ranged between 0.0073 h (0.4 min) and 0.47 h (28 min). After intravenous administration, the pharmacokinetic profile can be described by a two-compartment model. The distribution half-life t1/2 alpha is 0.18 +/- 0.20 h, the elimination half-life t1/2 beta is 2.06 +/- 0.90 h, the total body clearance (CL) amounts to 35.9 +/- 13.4 l h-1 and the steady-state volume (Vss) of distribution is 73.4 +/- 22.01. After oral administration, the pharmacokinetic profile can be described by a one-compartment model. The absorption half-life t1/2 abs is 0.19 +/- 0.22 h, and the elimination half-life t1/2 beta 1.90 +/- 0.16 h. This study with oral ergometrine shows such a large interindividual variability in bioavailability that the oral route of administration does not seem not to be the most reliable means of accurate dosing in preventing post-partum haemorrhage.

Administration, Oral↗
PubMed1994

Relationship between plasma and bone concentrations of cefuroxime and flucloxacillin. Three different parenteral administrations compared in 30 arthroplasties.

(i) The objective was to determine the range of bone levels of cefuroxime and flucloxacillin achieved after one intravenous (IV) administration of different dosages of cefuroxime and flucloxacillin. (ii) Six groups of five patients participated in the study. The first three groups (A-C) received respectively 1500 mg, 1000 mg, and 500 mg cefuroxime intravenously and the second three groups (D-F) received 2000 mg, 1500 mg, and 1000 mg flucloxacillin intravenously. (iii) Parenteral administration of cefuroxime and flucloxacillin resulted in measurable bone concentrations in all patients. (iv) Large inter-individual variation in bone concentration was observed. (v) The bone concentrations of IV cefuroxime were higher (1500 mg, p = 0.0057; 1000 mg, p = 0.0260) than those of flucloxacillin. The bone concentrations of cefuroxime and flucloxacillin were dose dependent.

Adult↗
PubMed1994

Combination of methotrexate and sulphasalazine vs methotrexate alone: a randomized open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy.

To compare efficacy, toxicity, and the pharmacokinetics of the combination of sulphasalazine (SASP) and methotrexate (MTX) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial. Forty RA patients with active arthritis despite adequate SASP therapy, were allocated randomly to regimes of either SASP+MTX or MTX alone. The patients were evaluated openly by a single observer for 24 weeks. In the first 15 patients using the combination, pharmacokinetics of MTX without and with SASP were studied. Thirty-eight patients completed the trial. The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group (-2.6 vs -1.3 respectively). The same pattern was seen concerning the other efficacy variables. There was no difference in the occurrence of toxicity. SASP had no influence on the pharmacokinetics of MTX. In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone, the toxicity of both therapies was similar. This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration.

Adult↗
PubMed1994

Formation and elimination of sulphamethoxazole hydroxylamine after oral administration of sulphamethoxazole.

The formation and elimination of sulphamethoxazole hydroxylamine in relation to the pharmacokinetics of the parent compound and its N4-acetyl metabolite were investigated in six healthy subjects after a single oral dose of 800 mg sulphamethoxazole. The apparent half-lives of sulphamethoxazole and its metabolites were approximately 10 h, indicative of formation rate-limited metabolism. The mean residence time of the hydroxylamine metabolite was 5.5 +/- 1.5 h. The renal clearance of sulphamethoxazole hydroxylamine was 4.39 +/- 0.91 l h-1. The urinary recovery of sulphamethoxazole accounted for 16.5 +/- 5.5% of the dose, N4-acetyl-sulphamethoxazole for 46.2 +/- 6.6% and the hydroxylamine metabolite for 2.4 +/- 0.8%. The remaining 35% of the dose was unaccounted for. Acetylator phenotype was determined using sulphadimidine. The renal excretion of sulphamethoxazole hydroxylamine was 1.9 +/- 0.9% in slow acetylators (n = 3) and 2.8 +/- 0.3% in fast acetylators (n = 3); for N4-acetyl-sulphamethoxazole the values were 48 +/- 6% and 44 +/- 8%, respectively. Sulphamethoxazole is metabolized, although to a limited extent, to a hydroxylamine metabolite. This metabolite may be important for the pathogenesis of adverse reactions.

Acetylation↗
PubMed1994

Morphine and morphine-glucuronide concentrations in plasma and CSF during long-term administration of oral morphine.

Concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were measured by h.p.l.c. in plasma and cerebrospinal fluid (CSF) samples from 16 patients with cancer receiving oral (controlled-release) morphine. There was a close correlation between plasma and CSF morphine concentrations (r = 0.94, P = 0.0001) and both correlated with drug dosage (r = 0.61, P = 0.013 and r = 0.74, P = 0.0001, respectively). M3G and M6G in plasma and CSF were correlated (r = 0.81 and r = 0.82, both P = 0.0001). No relationship was apparent between M plus M6G concentrations in the CSF and pain scores.

Administration, Oral↗
PubMed1994

Effect of urinary pH on the pharmacokinetics of salicylic acid, with its glycine and glucuronide conjugates in human.

We studied the effects of urinary pH on the kinetics of salicylic acid (SA) with its metabolites and assessed the contribution of alkaline hydrolysis of salicylic acid acyl glucuronide to the renal clearance of salicylic acid. Hydrolysis of SAAG in alkaline urine contributes marginally to the high renal clearance and excretion of salicylic acid, validating alkalinization of a patient with SA overdose. Under acidic urine conditions, salicylic acid (SA) had a terminal plasma t1/2 value of 3.29 +/- 0.52 hours while under alkaline urine conditions this t1/2 was significantly reduced to 2.50 +/- 0.41 hours (p = 0.0156). The total oral body clearance of salicylic acid under acidic conditions (1.38 +/- 0.43 l/h) is significantly lower than under alkaline urine conditions (2.27 +/- 0.83 l/h; p = 0.0410). The Km and Vmax values of SA, and its conjugates salicylic acid phenolic glucuronide (SAPG), salicyluric acid (SU) and salicyluric acid phenolic glucuronide (SUPG) did not differ statistically under acidic and alkaline urine conditions. The protein binding of SA was 93.8 +/- 1.0% and that of SU was 89.7 +/- 2.2% in vivo and in vitro. SUPG had a protein binding of 84.8 +/- 1.8%, while SAPG showed no protein binding at all. The renal excretion of salicylic acid depends strongly on the urinary pH. The percentage of the dose excreted unchanged increased from 2.3 +/- 1.5% under acidic conditions to 30.5 +/- 9.1% under alkaline conditions (p = 0.0006). Alkaline urine lowered by 50% the percentage of the dose excreted as SU (p = 0.0028), SAAG (p = 0.0013), and SUPG (p = 0.0296), while SAPG is only marginally lowered (p = 0.0589).(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗