A validated HPLC method for the simultaneous determination of naftidrofuryl oxalate and its degradation product (metabolite), naftidrofuryl acid: applications to pharmaceutical tablets and biological samples.

A simple, sensitive, and selective reverse phase-high performance liquid chromatography (RP-HPLC) method was developed and validated for the simultaneous determination of naftidrofuryl oxalate (NF) and its hydrolytic degradation product (metabolite), naftidrofuryl acid (NFA). Chromatographic separation was achieved on Spheri-5 RP-C8 (5 µm) (220 × 4.6 mm i.d.) column using a mobile phase composed of acetonitrile, 0.05 M sodium acetate and triethylamine (40 : 60 : 0.1, by volume) adjusted to pH 5.5 using glacial acetic acid. The mobile phase was pumped at flow rate 1.5 ml/min. The UV detector was set at 225 nm and quantification of the analytes was based on measuring the peak areas. The method was proved to be accurate and precise with linearity ranges of 0.1-25 and 0.2-25 µg ml(-1) for NF and NFA, respectively. The limits of detection were 0.03 and 0.04 µg ml(-1) for NF and NFA, respectively. The method was applied to serve three goals: (1) stability-indicating assay of the parent drug NF in its pharmaceutical formulation, (2) determination of the degradation product NFA down to a level of 0.005% in the presence of large excess of the parent drug, and (3) drug monitoring of naftidrofuryl and its metabolite, naftidrofuryl acid, in human plasma/urine samples taken from a healthy volunteer treated with 200 mg oral dose of naftidrofuryl oxalate. The proposed method proved to be accurate, precise, and reliable in all these application fields.

Influence of age on the pharmacokinetics of naftidrofuryl after single oral administration in elderly versus young healthy volunteers.

The aim of this study was to evaluate and compare the pharmacokinetics of naftidrofuryl (CAS 3200-06-4) after single oral administration of a 200 mg naftidrofuryl tablet (Praxilene) in Caucasian male and female elderly healthy volunteers versus young healthy volunteers. Thirty healthy volunteers were included in a randomised phase I trial in 3 parallel groups of 10 subjects aged 18-35 years (group 1), 60-70 years (group 2) and 70-80 years (group 3). Blood samples were taken over a period of 24 h after dosing for evaluation of the pharmacokinetics of naftidrofuryl. The Cmax, tmax, AUC0-t parameters were measured and t1/2 and AUC0-alpha were calculated by a model independent method. The mean (+/- SD) pharmacokinetic parameters of naftidrofuryl after single oral administration of 200 mg of naftidrofuryl for group 1 were as follows: tmax 3.5 h (median), Cmax 284 +/- 136 ng/ml, t1/2 3.69 +/- 1.30 h, AUC0-t 1865 +/- 905 h.ng/ml and AUC0-inf 2055 +/- 901 h.ng/ml; for group 2: tmax 2.75 h (median), Cmax 282 +/- 165 ng/ml, t1/2 3.03 +/- 1.08 h, AUC0-t 1783 +/- 1147 h.ng/ml and AUC0-inf 1856 +/- 1158 h.ng/ml; for group 3: tmax 2.5 h (median), Cmax 271 +/- 86 ng/ml, t1/2 3.50 +/- 1.29 h, AUC0-t 1742 +/- 544 h.ng/ml and AUC0-inf 1834 +/- 549 h.ng/ml. Statistical analysis was performed on the pharmacokinetic parameters with one-way ANOVA in order to compare each age group. The results of the pharmacokinetic and statistical analysis showed no significant difference between each age group. The mean pharmacokinetic parameters of naftidrofuryl after single oral administration of 200 mg of naftidrofuryl in the whole population were as follows: tmax 2.75 h (median), for Cmax 279 +/- 128 ng/ml, t1/2 3.41 +/- 1.22 h, AUC0-t 1797 +/- 870 h.ng/ml for AUC0-inf 1910 +/- 877 h.ng/ml. In conclusion, advanced age did not appear to influence the pharmacokinetic profile of oral naftidrofuryl, and therefore it is not necessary to adjust the dosage of naftidrofuryl in this population.

Platelet aggregation after naftidrofuryl application in vitro and ex vivo.

Naftidrofuryl has been shown to inhibit the interaction between platelets and damaged endothelium, which may lead to thrombosis and is mediated by the 5-hydroxytryptamine. (5-HT2) receptor. This study was designed to investigate the effects of naftidrofuryl on 5-HT induced platelet aggregation. In vitro experiments were carried out on platelets from healthy laboratory personnel. Naftidrofuryl (0.0625-100 microM) caused a continual increase in in vitro inhibition, whereby the inhibition at 0.0625 microM was already significant when compared to control (p < 0.05). The IC50 was approximately 10 microM induced aggregation. Subsequently, ex vivo effects of naftidrofuryl on 5-HT induced platelet aggregation of healthy volunteers together with naftidrofuryl plasma levels were measured. Twelve healthy volunteers received either 400 mg naftidrofuryl or placebo in this double-blind, crossover study. Blood samples for determination of aggregation and naftidrofuryl plasma levels were taken before, 0.5, 1, 2, 3, 4, 5, 6.5 and 9 h after medication application. One hour after application of 400 mg naftidrofuryl a maximal plasma level of approximately 380 ng/ml was measured. Under control conditions the aggregation (Vmax) increased from an arbitrary 100% at 8:00 am to about 150% by 10:00 am, remaining at this level until 5:00 pm. Application of 400 mg naftidrofuryl p.o. resulted in a 50% decrease in Vmax 2 h after drug application. Thereafter, the aggregation rose to the initial 100% value 4 h after drug application and remained at this level during the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

[Determination of naphthidrofuryl and naphthidrofurylic acid in human plasma using RP-HPLC and fluorimetric detection]. / Nekteré aspekty stanovení naftidrofurylu a naftidrofurylové kyseliny v lidské plazme metodou RP-HPLC s fluorimetrickou detekcí.

An analytical method was developed for the determination of naphthidrofuryl and its principle metabolite--naphthidrofurylic acid in human plasma by the RP-HPLC method with fluorimetric detection. The analytical method is based on a single extraction with a 5 ml mixture ether: hexane (1:1 by volume), with salting out by means of potassium chloride after which the organic phase after centrifugation, evaporation and reconstitution is sprayed on the reverse phase of HPLC and the separated substances are determined fluorimetrically (excitation 271 nm, emission 240 nm). Lonazolac served as the internal standard. The mobile phase consisted of 72% methanol, 1% triethylamine, 0.6% phosphoric acid. Optimization of the composition of the mobile phase from the aspect of the amino base, dependence of the percent content of methanol in the mobile phase and dependence of the recovery of substances on the composition of the extracting reagent are presented. The limit of detection was 4 ng/ml of plasma for naphthidrofuryl. The stability of compounds (a minimum of 2 months) and interference of some other drugs are shown.

Plasma concentrations and relative bioavailability of naftidrofuryl from different salt forms.

The relative bioavailability of the vasodilator naftidrofuryl from formulations containing its oxalate or citrate salt has been estimated using a specific HPLC assay, and a less specific fluorimetric assay, to measure plasma drug concentrations. The conclusions of the study were the same irrespective of the assay employed. The relative rate, but not the extent, of bioavailability of naftidrofuryl from the citrate salt (peak 1096 ng ml-1 at 0.76 h) was marginally greater (p = 0.003) than that from the oxalate salt (peak 922 ng ml-1 at 0.94 h). The degree of intersubject variability was similar after administration of either salt form. The mean half-life of naftidrofuryl was 1.8 h and its mean residence time was 2.5 h.

[Pharmacokinetics of naftidrofuryl in multimorbidity in geriatric patients]. / Pharmakokinetik von Naftidrofuryl bei multimorbiden geriatrischen patienten.

The present pharmacokinetic study of a drug used in geriatric patients with multiple diseases reveals that the half-life in the elderly was extended for about three times as long as in the corresponding control group. There are significant positive as well as negative correlations between the kinetic data and routine parameters of the metabolism. These statistical correlations should be controlled by experimental studies.