J. X. de Vries

Benzbromarone disposition and uricosuric action; evidence for hydroxilation instead of debromination to benzarone

SummaryBenzbromarone is one of the main uricosuric drugs currently used. We determined plasma concentrations of benzbromarone, bromobenzarone, and benzarone and 24 hour uric acid excretion in ten healthy individuals following fasting application of two different non-micronised benzbromarone brands. In addition we explored the influence of adjusting urinary pH to near neutral values and of concomitant food intake. Benzbromarone was more rapidly absorbed from the test preparation than from the reference preparation; the extent of systemic availability did not differ significantly. Urinary pH adjustment had no clearcut effect, whereas food intake retarded drug absorption (even though not significant because of the variability of the data). Binding of benzbromarone to plasma proteins exceeded 99%. Bromobenzarone and benzarone were not detectable and are unlikely to be major metabolites of benzbromarone. Instead we found two other compounds suggestive of metabolites, one of them being monohydroxilated benzbromarone. The plasma concentrations of the parent compound in one subject exceeded those of the rest of the group, possibly indicating genetic differences in drug metabolism. The uricosuric effect was not related to benzbromarone plasma concentrations.

Disposition and uric acid lowering effect of oxipurinol: comparison of different oxipurinol formulations and allopurinol in healthy individuals

We have investigated the disposition and plasma uric acid lowering effect of oxipurinol in ten healthy individuals following oral administration of three different formulations of oxipurinol and of allopurinol in equimolar doses. The reduction of plasma uric acid was clearcut up to 48 h. As estimated from plasma AUC0-∞, Cmax, tmax, tlag, and urinary drug excretion, a conventional rapid release preparation of oxipurinol sodium was clearly superior to oxipurinol as free acid and to enteric coated microtablets of oxipurinol sodium. Plasma oxipurinol concentrations following a single dose of the conventional formulation of oxipurinol sodium were approximately 25% lower than those observed after an equimolar dose (300 mg) of allopurinol, but mean Cmax reached the value reported to be necessary for 90% inhibition of xanthine oxidase. Since prolonged administration will result in accumulation of oxipurinol because of its slow elimination, this type of oxipurinol formulation can be expected to meet the therapeutic requirements for a drug to lower plasma uric acid.

Phenprocoumon metabolites in human plasma; characterization by HPLC and GC-MS

SummaryPooled plasma from patients receiving phenprocoumon anticoagulant therapy was extracted and the following substances were characterized: phenprocoumon, and its 7-hydroxy,4′-hydroxy and 6-hydroxy derivatives; they were identified by HPLC and after methylation by quartz capillary GC-MS using the electron impact and selective ion monitoring modes. This is the first occasion when phenprocoumon metabolites have been identified in plasma; they were unconjugated and in much lower concentrations (43.2 and 2 ng/ml for the 7,4′ and 6-hydroxy derivatives, respectively) than the original compound (2000 ng/ml).

Lack of effect of cimetidine on action of phenprocoumon.

SummaryIn patients on oral warfarin, nicoumalone and phenindione an increase in the anticoagulant effect has been described during concomitant treatment with cimetidine. Therefore the effect of cimetidine on the steady state dynamics of phenprocoumon has been investigated in ten outpatients. No change in the anticoagulant effect of phenprocoumon was observed during or after two weeks on cimetidine, as measured by the thrombotest coagulation method, prothrombin time, fibrinopeptide A concentration and plasma phenprocoumon level. The data show that cimetidine does not interact with the metabolism of phenprocoumon in contrast to warfarin. Thus, phenprocoumon maintenance therapy when combined with concomitant cimetidine treatment can be considered not to carry an increased risk of haemorrhagic complications.

Bioequivalence of allopurinol preparations: to be assessed by the parent drug or the active metabolite?

SummaryAllopurinol is converted almost completely into a single active metabolite, oxipurinol, which has the same therapeutic pattern but a much longer elimination half-life than the parent compound. Therefore both allopurinol and oxipurinol were evaluated in our bioequivalence study in healthy volunteers comparing two allopurinol brands. Bioequivalence determination was based on the 90% confidence intervals (CI) of the area under the plasma concentration time curve from time zero to infinity (AUC0−∞), of the area from time zero to the last measurable plasma concentration (AUC0−t (last)), and Cmax. Because of the lack of compound-specific criteria we used conventional limits for the bioequivalence range. Under these conditions the brand chosen as test preparation was judged to be bioequivalent to the reference form with respect to the extent of bioavailability, AUC0−∞, and AUC0−(last) of the parent drug. The CI of Cmax of allopurinol slightly exceeded the upper limit of 130%, so that bioequivalence was not confirmed with regard to the rate of bioavailability of the parent compound. The CI values of both AUC and Cmax of the active metabolite were tighter than those of allopurinol. In addition, the CI values of Cmax of oxipurinol were smaller than those of the corresponding AUC. As a consequence the test drug can clearly be accepted as bioequivalent, based on metabolite data. Since the active metabolite is of greater therapeutic significance than the parent drug, assessment of the bioequivalence of allopurinol preparations needs to be based on oxipurinol rather than allopurinol. Our data provide further evidence that establishing compound-specific criteria is required for bioequivalence evaluation in drugs with a single active metabolite.

Variation of benzbromarone elimination in man — a population study

SummaryThe plasma benzbromarone concentration-time profile in a healthy subject who retained the compound much longer than other individuals is described. The data suggested that determination of the 24 h plasma concentration of the parent drug after a single oral dose of 100 mg benzbromarone would be an appropriate procedure to determine the elimination phenotype. Based on this procedure, 148 of 153 healthy individuals (97%) in a population study were found to eliminate benzbromarone rapidly. In one subject the 24 h benzbromarone plasma concentration was very similar to the that observed in the individual who had been more fully characterized. Four participants gave intermediate results. The data are compatible with a bimodal or trimodal distribution of different benzbromarone elimination phenotypes.

Interaction of allopurinol and hydrochlorothiazide during prolonged oral administration of both drugs in normal subjects

The interaction of allopurinol (300 mg/day) and hydrochlorothiazide (50 mg/day) was studied in seven healthy male volunteers during prolonged coadministration of the two drugs using defined dietary conditions. A formula diet was administered with the allopurinol throughout the 24-day study, while hydrochlorothiazide was added during days 11–21. After the addition of hydrochlorothiazide both plasma uric acid and plasma oxipurinol rose for 6 days – 24% and 30%, respectively, compared to steady-state levels during allopurinol alone (P < 0.01 each). In neither substance were variations in renal excretion significant. By the end of combined treatment (day 21), the changes induced by hydrochlorothiazide had already been reversed to a considerable extent. It is concluded that both in normal individuals and in patients with normal renal clearance of uric acid the effect of hydrochlorothiazide on the plasma concentration and renal excretion of oxipurinol is small. When taking both drugs, there is no increased risk during long-term treatment, and a risk is even questionable during the first days.

Benzbromarone hydroxylation in man : defective formation of the 6-hydroxybenzbromarone metabolite

SummaryTo determine the elimination phenotype of the uricosuric agent benzbromarone 100 mg of the drug was administered as a single oral dose to 11 volunteers on a formula diet; plasma concentration-time profiles of the parent drug and the main metabolites M1 (1′-hydroxybenzbromarone) and M2 (6-hydroxy-benzbromarone) were measured by high-performance liquid chromatography for 168 h. Of the 11 subjects 2 showed higher plasma concentrations and delayed elimination of benzbromarone and metabolite M1 but reduced formation of metabolite M2 compared to the other 9 subjects. However, the plasma concentration-time profiles of the metabolites in these two slow eliminators, termed type 2, differed from those of a poor eliminator characterized during a previous study; the latter, termed type 1, eliminated benzbromarone as well as both metabolites M1 and M2 slowly. The differences in the elimination of benzbromarone and its metabolites are probably caused by differences in the activities of the cytochrome P450 mono-oxygenase isozymes. The results show that determination of the phenotype solely by measurement of the 24-h benzbromarone plasma concentration does not unequivocally characterize slow benzbromarone eliminators; additional plasma concentration-time profiles of the parent drug and metabolites are necessary. Metabolite M2 is characterized as 6-hydroxybenzbromarone; the formation and elimination of the chiral metabolite M1 is enantioselective.

Lack of accumulation of midazolam in plasma and lipoprotein fractions during intravenous lipid infusions in patients on artificial respiration.

SummarySeverely ill patients often require total parenteral nutrition including intravenous liqid emulsions concurrently administered with lipophilic drugs. Therefore we investigated whether therapeutic application of a mixed medium chain/long chain triglyceride infusion affects the disposition of midazolam necessary for sedation in patients on artificial respiration. The concentrations of midazolam were measured in unfractionated plasma, and in lipoprotein fractions isolated from ex vivo blood samples, including determination of triglycerides and cholesterol; the albumin level was also analysed.Midazolam in the VLDL fraction was only 0.246 μg·ml−1, whereas the total plasma concentration averaged 1.101 μg·ml−1, and the midazolam content of the LDL plus HDL fractions amounted to 1.771 μg·ml−1. Albumin in these lipoprotein fractions was just as unequally distributed. A lipid infusion resulted in a significant elevation of total triglycerides from 157 to 221 mg·dl−1 and VLDL-triglycerides from 77 to 155 mg·dl−1. The triglyceride content of the LDL plus HDL fraction rose from 102 to 139 mg·dl−1. At the same time the midazolam concentration in unfractionated plasma and in the VLDL and the LDL + HDL fractions decreased to 0.899 μg·ml−1, 0.130 μg·ml−1, and 1.265 μg·ml−1, respectively. Cholesterol and albumin concentrations were not affected.The data show for the first time that a significant increase in plasma triglycerides during an intravenous lipid infusion does not result in accumulation of midazolam in lipoproteins, probably because albumin binding of the drug is very strong. The lack of midazolam trapping is important with respect to the safety of concurrent use of lipophilic drugs and intravenous lipid infusions.

The effects of a combination of cigarette smoking and oral contraception on coagulation and fibrinolysis in human females

SummaryOral contraception as well as cigarette smoking influence haemostasis. The simulataneous effect of both on blood coagulation and fibrinolysis was studied in nine female smokers. While continuing oral contraception after a 4-week abstinence from smoking the concentration of fibrinogen, antithrombin III and alpha1-Antitrypsin decreased (P<0.01 orP<0.04) and of plasminogen increased (P<0.03). The other coagulation parameters remained unchanged. Although all determinations of these parameters were in the normal range, the observed trends were statistically significant. The concentrations of the fibrinopeptide A and B 15–42 did not differ. It is concluded that the observed alteration is caused by cessation from cigarette smoking.