Pharmacokinetics and distribution of the new antihypertensive agent pinacidil in rat, dog and man.

1. The antihypertensive agent pinacidil was rapidly, and almost completely, absorbed following oral administration of 0.5 mg/kg of the [14C]pinacidil monohydrate to rats and dogs. The half-life was about 1 and 2 h in the two species, respectively. A bioavailability of 80% of unchanged pinacidil in the rat suggests a first-pass effect in this species. 2. After oral and intravenous administration of [14C]pinacidil about 85% of the radioactivity was recovered in the urine and 15% in the faeces in rats and dogs; 80-90% was excreted during the first 24 h. Autoradiographic studies in the rat showed similar distributions after oral and intravenous administration. 3. An oral dose of 5 or 10 mg pinacidil monohydrate was rapidly absorbed in healthy volunteers and had a pharmacokinetic profile very similar to that found in rats and dogs. Concomitant food ingestion did not change the bioavailability of the drug.

Metabolism of the new antihypertensive agent pinacidil in rat, dog and man.

1. The antihypertensive agent pinacidil is eliminated from the body mainly by biotransformation in the liver, followed principally by renal excretion of the metabolites. 2. The metabolism and elimination of pinacidil is similar in rat, dog and man, and is independent of the route of administration. 3. After an oral dose, the 24 h urinary excretion of unchanged pinacidil is 13, 4, and 5% in rat, dog and man, respectively. Faecal excretion in the rat and dog is 2 and 4%. 4. In rat, dog and man the main biotransformation product is the pyridine-N-oxide of pinacidil. Following oral administration of pinacidil, 40, 54 and 54%, respectively, is excreted in the urine as the N-oxide during the first 24 h, and less than 1% in the faeces in rat and dog. 5. Three unidentified minor metabolites were found in plasma, urine and faeces in rat and dog. 6. The major metabolite, the pyridine-N-oxide of pinacidil, has an anti-hypertensive potency about a quarter of that of pinacidil. In animals and human volunteers with normal kidney function, however, the plasma concn. of the N-oxide are always lower than those of the parent compound, so that the metabolite contributes little to the antihypertensive effect of pinacidil.

The effects on urinary kinin excretion of oral salt and water loads in dogs.

Ten dogs received 1 l of 37 degrees C tap water by stomach tube. Urine flow rate increased from 17 +/- 6 ml in the control hour to 285 +/- 25 ml in the second hour following the water intake. The diuresis was paralleled by increased urine kinin excretion from 23 +/- 9 ng/h to 94 +/- 17 ng/h. Urine kallikrein and urine sodium excretions remained unmodified. In seven dogs urine sodium excretion was increased from 0.87 +/- 0.22 mmol/h to 14.9 +/- 1.9 mmol/h by intragastric administration of 2% NaCl. Urine flow moderately increased from 15.1 +/- 2.5 ml/h to 64.3 +/- 15.0 ml/h. Urine kinin excretion was unchanged. The results suggest a relationship between high rates of urine flow and urinary kinin excretion.

Prostaglandins, a link between renal hydro- and hemodynamic in dogs.

An increase of the intrarenal pressure to 40 mmHg induced by ureteral constriction or by kidney compression is shown to be followed by increased renal blood flow in anesthetized dogs. This hyperemia is probably the result of enhanced intrarenal prostaglandin activity since it is followed by increased urinary prostaglandin E excretion and is abolished by indomethacin pretreatment. The increase of renal blood flow seems to be due to dilation of the afferent arteriole in order to maintain the filtration pressure. The glomerular filtration rate is thus severely depressed in indomethacin pretreated dogs. Urine and electrolyte excretion is comparably redcued during elevated intrarenal pressure in non-pretreated and in indomethacin pretreated dogs, which suggests that factors other than glomerular filtration rate are involved. Urine osmolarity is positively correlated with renal blood flow, and urine osmolarity increases during elevated intrarenal pressure in non pretreated dogs, whilst urine osmolarity remains unchanged in dogs pretreated with indomethacin.