Radioimmunoassay of acipimox in human plasma and urine.

A radioimmunoassay was developed for the determination of acipimox (5-methylpyrazinecarboxylic acid 4-oxide) in human plasma and urine. Acipimox was conjugated to bovine serum albumin through a spacer with 4 carbon atoms, and repeatedly injected into rabbits. Antisera raised in these animals were highly specific and virtually no cross-reaction was observed with 5-methylpyrazinecarboxylic acid and nicotinic acid. Despite the low specific activity of the labelled antigen used, concentrations of acipimox in human plasma and urine as low as 40 ng/ml could be determined. The intra- and inter-assay coefficients of variation ranged between 4.32-6.25% and 6.19-11.55% respectively, and mean recovery of the compound spiked to plasma was 100-103%. The method was applied to determine plasma levels and urinary excretion of acipimox after oral doses of 150 mg and 250 mg to four volunteers.

High-performance liquid chromatographic method for pharmacokinetic studies on the new anthracycline 4-demethoxydaunorubicin and its 13-dihydro derivative.

The anthracyclines are a group of antitumoral antibiotics with significant clinical efficacy. Among the new anthracycline derivatives, 4-demethoxydaunorubicin showed interesting biological properties in terms of both spectrum of activity and therapeutic index and was recently introduced in clinical trials. The present paper describes the analytical method developed to investigate the pharmacokinetics of this derivative. The method consists of the extraction of 4-demethoxydaunorubicin and its 13-dihydro metabolite from plasma with chloroform--1-heptanol (9:1) and re-extraction with 0.3 M phosphoric acid, separation by high-performance liquid chromatography and quantification by sensitive fluorescence detection. Plasma level curves obtained from cancer patients treated with the drug are shown.

Bioavailability and pharmacokinetics in man of acipimox, a new antilipolytic and hypolipemic agent.

Two separate studies were performed: in the first study for healthy male volunteers received three single oral doses (150, 250 and 400 mg) of 5-methylpyrazine carboxylic acid 4-oxide (acipimox) according to a randomized sequence. Plasma levels of the drug were determined by RIA and urinary excretion by HPLC. In the second trial the effect of food on the drug bioavailability and pharmacokinetics during repeated administration was investigated in six volunteers. The RIA method was adopted to measure plasma and urine levels. Acipimox was rapidly and almost completely absorbed after the three single doses. About 90% of the administered dose was recovered as unchanges drug in urine collected up to 24 h. Peak plasma levels, area under plasma levels curves and urinary excretion were linearly related to the administered dose. The presence of food in the gastro-intestinal tract did not adversely affect the bioavailability of the drug. No significant changes were noted in the rate of elimination after 6 days of treatment with 250 mg t.i.d. Plasma levels determined after the 19th dose were in good agreement with those predicted on the assumption of linear pharmacokinetics and a one-compartment open model, with a half-life of about 2 h.

Radioimmunoassay of glipizide in human plasma.

A simple, sensitive radioimmunoassay has been developed for the direct determination of glipizide in human plasma. Antisera raised in rabbits immunized with a glipizide analogue conjugated to bovine serum albumin were highly specific, the two main metabolites, 3, cis-hydroxycyclohexyl derivative and 4,trans-hydroxycyclohexyl derivative, having cross reactivities of 0.73% and 1.66%, respectively. The method can measure amounts as small as 1 ng/ml. The intra- and inter-assay coefficients of variation lay between 2.98-5.79% and 2.35-8.66%, respectively. The mean recovery of glipizide added to plasma was 99-105% over the range 1-500 ng/ml. The method was employed to determine plasma levels in six subjects after administration of a 5 mg tablet of glipizide. The results were in accordance with those found after administration of the same dose of radiolabelled glipizide to two other subjects.

Pharmacokinetics and metabolism of a new beta-adrenergic blocking agent, the 1, ter-butyl-amino-3-(1,2,3,4-tetrahydro-1,4-ethano-8-hydroxy-5-naphthoxy)-2-propanol (K 5407).

A beta-blocking agent, the 1,ter-butylamine3-(1,2,3,4-tetrahydro-1,4-ethano-8-hydroxy-5-naphthoxy)-2-propanol (K5407) was synthesized with 14C and 3H and its pharmacokinetics in the dog and man were investigated after i.v. and oral administration. K5407 was rapidly absorbed after oral dosing and plasma peaks were within 1 hour. Concentrations of unchanged compound were found to be very small. After i.v. injection the levels decreased with a half-life of 2-3 hours. Excretion was mainly in the urine and amounted to about 72% of the dose in the dog and about 85% in man for both administration routes. Tissue radioactivity distribution studies in male and in pregnant mice after i.v. injection showed rapid body diffusion, passage through the blood-placenta barrier and no localization in the central nervous system. The metabolic process in dog and human urine was studied. Little unchanged compound was found (5% in the dog and 13% in man after i.v. injection and about 1% in both species after oral dosing). Conjugation processes represented the main route of biotransformation. Five metabolites, resulting from side chain degradation of the compound, were identified in dog urine and in trace quantities in human urine.

Pharmacokinetics and metabolism of indoprofen in the hamster.

2-[p-(1-Oxo-2-isoindolinyl)phenyl]propionic acid (indoprofen) is rapidly absorbed after oral administration (2 mg/kg) to male and female hamsters. Peak plasma levels of about 12-13 microgram/ml are reached within 1 h of dosing. Plasma concentrations in males and females are similar until 4 h but different at subsequent observation times. The half-life of indoprofen in plasma is approximately 7 h for males and 16 h for females. In experiments with 14C-labelled compound, radioactivity is mainly excreted in the urine: 94% of the dose in 6 days for males and 73% in 5 days for females. The females also excrete a significant amount of the drug (22%) in the faeces, probably via the bile. Residual radioactivity in female carcasses on the 5th day represents 1% of the dose. The main excretory product is the unchanged drug as such (about 35% and 21%, respectively, in 0-24 hour urine for males and females) and as glucuronic acid conjugate (29% and 12%). Small amounts of 5- and 6-hydroxy-isoindolinyl derivatives, and of two metabolites whose structures have not been identified, are also found in the urine of the animals of both sexes.

Tissue distribution of 14C-indoprofen in the rat.

The tissue distribution of 14C-labelled 2-[p-(1-oxo-2-isoindolinyl)phenyl)propionic acid (indoprofen) after i.v. injection was studied in male and pregnant rats by whole-body autoradiography. Distribution was characterized by a rapid localization in the liver, kidneys and lungs. A significant amount of radioactivity found in the intestinal contents suggested biliary excretion. There was no indication of retention of the drug in the brain. In pregnant rats, radioactivity crossed the blood-placenta barrier to a moderate extent and low concentrations were found in foetuses.

Gastro-intestinal blood loss during administration of indoprofen, aspirin and ibuprofen.

The acute effect of three non-steroidal anti-inflammatory drugs, ibuprofen, acetylsalicylic acid (ASA) and indoprofen, on faecal blood loss was investigated in 15 subjects by means of 51Cr-labelled erythrocytes. Ibuprofen (900 mg/day for 5 days) and indoprofen capsules and tablets (300 mg and 600 mg/day for 5 days, respectively) slightly increased the amount of blood eliminated in faeces. The increase was of the same order of magnitude for both doses of indoprofen. ASA (1,500 mg/day for 5 days) caused about a 6-fold increase in blood loss. Four days after withdrawal of ASA, faecal blood was still about twice as high as in faeces of subjects given ibuprofen and indoprofen. The method appears sensitive and reliable for comparison of the immediate effect of anti-inflammatory drugs on gastro-intestinal mucosa.