Pharmacokinetics of mono-3'- and mono-4'-0-(beta-hydroxyethyl)-rutoside derivatives, after single doses of Venoruton powder in healthy volunteers.

BACKGROUND: Venoruton is a standardised mixture of O-(beta-hydroxyethyl) rutosides (HR) used for the relief of oedema and related symptoms in patients with chronic venous insufficiency. OBJECTIVES. The primary objective was to evaluate the pharmacokinetic parameters, in particular the rate and extent of absorption (bioavailability) of two markers of Venoruton: mono-3'-HR and mono-4'-HR derivatives [glucuroconjugated forms (HG)], analysed in their deconjugated form as O-(beta-hydroxyethyl)-quercetin (HQ): mono-3'-HQ and mono-4'-HQ, and to investigate dose proportionality. A secondary objective was to evaluate the general safety of the different dosages. METHODS: In this open, single-dose, randomised, four-way, crossover study, 16 healthy volunteers received four different oral doses of Venoruton powder (0.5, 1, 2 or 4 g). Eighteen blood samples were obtained between 10 min pre-dose and 120 h post-dose. RESULTS: Peak plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) of mono-3'-HQ were or tended to be proportional to the dose between 1 g and 4 g. The dose proportionality could be extended to the 0.5-g dose, although C(max) and AUC were not always estimable at that dose level (due to the low number of data points above the limit of quantification). For mono-4'-HQ, the increase of C(max) and AUC was also or tended to be proportional to the dose over the whole tested range (0.5-4 g). Time to peak concentration of both Venoruton derivatives remained unaffected by the administered dose. The elimination half-life of both molecules was very similar with the three highest doses. It was shorter with the 0.5-g dose but was not accurately estimated (or even not estimable in some subjects) due to the low number of points above the limit of quantification. CONCLUSIONS: The bioavailability of both Venoruton derivatives (mono-3'-HQ and mono-4'-HQ) tended to be proportional to the dose. The rate of appearance and the elimination half-life of both molecules were not modified with the administered dose. The different doses of the study medication were safe and well tolerated. Mono-3'-HQ and mono-4'-HQ are therefore new bioanalytic and pharmacokinetic markers for Venoruton.

In vitro metabolism by human skin and fibroblasts of retinol, retinal and retinoic acid.

The metabolism of radio-labelled retinol, retinal and retinoic acid by fresh human skin as well as by human dermal fibroblasts have been investigated in vitro. Surgically removed human skin biopsies were placed at the air liquid interface, and treated topically for 24 h with retinoids. At the end of the treatment period, epidermis and dermis were separated by heat. Epidermis, dermis and medium were subsequently extracted and resulting fractions were analysed by HPLC. Dermal fibroblast cultures were treated and analysed in a comparable manner. Topical application of retinoids resulted in gradient concentrations within the skin. For each fraction, metabolites and unchanged product proportions were determined by HPLC. After treatment with retinol and retinal, low but significant amounts of retinoic acid were detected in the epidermis, as well as in the dermis (30 pmol to 90 pmol). In comparison, treatments with retinoic acid itself, led to higher level of retinoic acid in the epidermis and in the dermis (respectively 2050 and 420 pmol). Cultured human dermal fibroblasts, treated with retinol and retinal, formed retinoic acid as well as several other metabolites (retinol esters, reduction of retinal to retinol...). Taken together, our results are consistent with an action of retinol or retinal on the skin via a retinoic acid formation and a metabolic function of the dermis.

Pharmacokinetic study of 14C-letosteine in man after oral intake and steady-state.

Based on previous animal and on preliminary human results a further human study was performed in order to confirm the relevant pharmacokinetic parameters and the lack of accumulation of letosteine after repeated administrations. Thus, six healthy male volunteers were given a single oral dose of 50 mg (100 microCi) 14C-letosteine in form of gelatine capsules. A treatment lasting 11 days to obtain a steady-state was started three days later with three similar daily oral doses of unlabelled letosteine. Then, one capsule of 14C-letosteine was administered again. The radioactivity of blood, plasma, urine and expired air was measured at regular intervals after both radioactive doses. Several pharmacokinetic parameters were calculated for the single oral intake and for the oral intake at steady state. The results show a good absorption rate of letosteine since about 90% of the dose was found in the urine. Elimination was biphasic, with half-lives of about 1 and 4 hours in blood and plasma. No striking differences were recorded between the single oral intake and the oral intake at steady state for the various parameters assessed: Cmax, Tmax, AUC, Aeurine and AeCO2. It was therefore concluded that repeated doses of letosteine did not influence the absorption, the distribution, the metabolism and the elimination processes.

Micromethod for the determination of glycosaminoglycans in the serum. Results from the serum of healthy and varicose subjects.

Serum glycosaminoglycans (GAG) were isolated from 1 ml of serum by a modification of the method of Y. Emura and T. Mukuda (J. Jap. Biochem. Soc., 45 (1973) 30). The extraction was carried out as quantitatively as possible and the hexuronic acids in the GAG were measured with m-hydroxydiphenyl. This method for determination of the GAG is relatively easy, easily reproducible and requires no more than two days. Its application in clinical chemistry may prove to be useful in the detection of diseases involving connective tissue. A study was carried out with serum samples from 34 patients suffering from serious varicose conditions, compared with samples fro 30 healthy subjects. The mean concentration of GAG in the serum of healthy persons was 0.602 +/- 0.108 (p smaller than 0.0005). There were not, however, any significant variations between patients suffering from serious varices without trophic changes and those with comparable varices accompanied by trophic changes, such as phlebitis, thrombosis and ulcers.