Biologic actions and pharmacokinetic studies of auranofin.

The preclinical profiles of auranofin (Ridaura), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate, gold thioglucose, and their respective ligands were compared. Auranofin was more effective than gold sodium thiomalate in suppressing inflammation and stimulating cell-mediated immunity. In contrast to gold sodium thiomalate and gold thioglucose, auranofin inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions. The respective ligands were without significant biologic activity. In rats, a higher fraction of gold was associated with blood cells after auranofin administration than after gold sodium thiomalate. The absorption, distribution, metabolism, and excretion of auranofin are uniquely different from other gold compounds.

Pharmacokinetics of auranofin in animals.

Gold from orally administered auranofin (AF) was absorbed 17-23% in rats and 15-38% in dogs. Gold was highly bound to blood cells and plasma proteins. Gold terminal half life was 1.2-1.8 days in rat blood and plasma (measured for 7 days post dose) and 19.5 days in the dog (measured for 42 days). Excretion of gold (rat and dog) was via feces (84 and 81%) urine (10 and 16%) and bile (3% of dose). Rat tissue levels of gold were highest in the kidney. Evidence indicated that AF was rapidly degraded to triethylphosphine oxide with the remaining molecular fragments postulated to be a protein-gold complex and acetylthioglucose.

Metabolism of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, a phenylethanolamine N-methyltransferase inhibitor. II. Species difference in metabolism and synthesis of its metabolites.

1. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (DCTQ), a potent reversible inhibitor of phenylethanolamine N-methyltransferase, was well absorbed, readily metabolized and excreted mainly in urine. 2. Its pathways of metabolism in rats and dogs were markedly different. In the dog, N-methylation was followed by N-oxidation to give the corresponding N-methyl-N-oxide as the final metabolic product. This was not observed in the rat. 3. In the rat, major pathways are aromatization of DCTQ to the corresponding isoquinoline and subsequent hydroxylation in the hetero ring to all three possible isomeric hydroxy-isoquinolines. 4. Authentic metabolites were synthesized for comparison with metabolites isolated from urine.

Correlation of [14C]muscimol concentration in rat brain with anticonvulsant activity.

Muscimol, an in vivo and in vitro GABA agonist, has anticonvulsant activity against bicuculline-induced seizures when given systemically to rats. To determine whether parent compound or a metabolite possessed the anticonvulsant activity, experiments were performed with [14C]muscimol. Anticonvulsant activity was determined by the percent of animals protected against tonic forelimb extension induced by bicuculline. Brain and urine were analyzed for unchanged [14C]muscimol by thin-layer chromatography. The time course of anticonvulsant activity and [14C]muscimol concentration in brain after intravenous injection were similar. Peak brain concentration of [14C]muscimol and maximal protection against bicuculline-induced seizures occurred simultaneously. These data suggest that intravenously administered [14C]muscimol rapidly penetrates brain tissue and parent compound is responsible for antagonism of bicuculline-induced convulsions.

High-pressure liquid chromatographic analysis of ticrynafen and one of its metabolites in urine and serum.

A method is described for the extraction of ticrynafen, a new hypotensive agent, and its reduced metabolite from serum and urine. Drug-related material is extracted from biological fluids with ether under strongly acidic conditions and then back-extracted into an alkaline aqueous phase, which is subjected to high-pressure liquid chromatographic analysis. Separations are performed on a reversed-phase column with a mobile phase consisting of phosphate buffer-acetonitrile. This accurate and reproducible method measures serum concentrations of ticrynafen and its reduced metabolite as low as 1.0 and 0.4 microgram/ml, respectively.

Studies with a PNMT inhibitor.

DCTQ (SK&F 64139) is a potent inhibitor of both adrenal and central nervous system (CNS) phenylethanolamine N-methyltransferase (PNMT). In animal studies, a plasma level of 0.35 microgram/ml was associated with 50% inhibition of both adrenal and central PNMT. We performed single-dose phase I studies with DCTQ in man. Plasma drug levels up to 6.26 microgram/ml were readily obtained. There were few subjective and no objective clinical changes. DCTQ did not alter blood pressure or cause CNS symptoms in man. Furthermore, resting plasma and urinary catecholamines did not change after DCTQ. The study suggests that acute inhibition of PNMT under resting conditions is without significant clinical effect.

Distribution in normal and inflammatory tissue of a new semisynthetic cephalosporin, SK&F 75073.

SK&F 75073 is a new cephalosporin with broad spectrum antibacterial activity. SK&F 75073-14C and cefazolin-35S were administered separately to groups of rats as a single intramuscular dose of 20 mg/kg. Tissues with highest drug levels 15 minutes following dose were as follows: (SK&F 75073/cefazolin levels), kidney - 86/70 microgram/g, liver - 33/22 microgram/g, lung - 29/17 microgram/g, heart - 23/10 microgram/g, adrenal - 13/7 microgram/g. Plasma levels at peak were 134 microgram SK&F 75073/ml (half-life, 1.9 hours) and 72 microgram cefazolin/ml (half-life, 0.75 hours). Dose excreted in 24 hours was: SK&F 75073, urine 66% and feces 27%; cefazolin, urine 96% and feces 2%. Both antibiotics were also administered, at 20 mg/kg, to rats with the carrageenan-induced inflammatory pouches. Exudate from these pouches contained from 2 to 10 times more SK&F 75073 than cefazolin. Radioassay and bioassay of these substances in the exudate gave similar results. Serum protein binding ranged from 96 approximately 98% for SK&F 75073 and 34 approximately 69% for cefazolin. Data indicated that highly protein bound SK&F 75073 enters tissues and tissue fluid to a greater extent than the lesser bound but therapeutically proven antibiotic agent cefazolin.

Bioavailability of cimetidine in man.

The bioavailability of parenteral cimetidine was tested in 12 volunteers in a balanced three-way crossover study. Blood levels and urinary excretion were compared after intramuscular and intravenous injection and oral administration of 300 mg of cinetidine. The results indicated that the intramuscular and intravenous routes are virtually interchangeable for parenteral cimetidine, and that the oral liquid, although exhibiting a reduced area under the blood level curve as compared with the parenteral doses, nevertheless demonstrated equivalence with respect to the time the blood level remained above 0.5 microgram per ml. The 300-mg cimetidine tablet formulation was found in another group of 12 volunteers to be bioequivalent to a 300-mg dose of oral liquid.

High-pressure liquid chromatographic analysis of cimetidine, a histamine H2-receptor antagonist, in blood and urine.

A method is described for extraction of cimetidine, a histamine H2-receptor antagonist, from whole blood and urine with subsequent analysis by high-pressure liquid chromatography (HPLC). The drug is extracted from biological fluids with 1-octanol and back-extracted into dilute acid and then into a small volume of ethanol by saturation with potassium carbonate. HPLC analysis is performed on a column of 5-micrometer silica with a mixed mobile phase consisting primarily of acetonitrile. The method measures concentrations of cimetidine as low as 0.05 microgram/ml and is reproducible. Blood levels and urinary excretion data obtained with the analytical procedure are given for a group of human subjects who received 200-mg oral doses of cimetidine.

Use of anemic piglet to assess bioavailability of iron from oral iron preparations.

Except for methods using long-lived iron isotopes, there are no reliable means for assessing the bioavilability of iron from oral preparations in human subjects. Use of the anemic piglet as an alternative means was studied. When piglets were made anemic on a commercial milk diet and then dosed with solutions of 1, 2, and 5 mg/kg of ferrous sulfate/day, a dose-related recovery of hematocrit and hemoglobin levels resulted. The most sensitive dose range for use in a bioavailability study of iron was between 1 and 2 mg of iron/kg/day when using these parameters. A study carried out using this method indicated that the iron from a delayed-release capsule and from a ferrous sulfate solution was equally bioavailable. Hemoglobin and hematocrit recovery rates of the anemic piglet were shown to be reliable and sensitive indicators of the bioavailability of iron from various iron dosage forms.