Practolol: aspects of its metabolism and ocular binding in the hamster.

The metabolism and ocular binding of practolol were investigated after oral administration of 14C-practolol to hamsters treated with three modifiers of mixed-function oxidase activity: piperonyl butoxide, cobalt chloride or phenobarbitone. The major urinary metabolites of practolol were 3-hydroxypractolol and polar metabolites which included glucuronide conjugates. A number of unidentified metabolites constituted a minor portion of urinary radioactivity. Each pretreatment modified both the urinary excretion pattern (0-24 h) of practolol and its metabolites and also the metabolite profile of eye extracts 24 h after an oral dose. None of the modifiers of mixed-function oxidase activity had any significant effect on the ocular binding (both extractable and non-extractable components) of practolol and its metabolites. The results indicated that the non-extractable component was neither practolol nor 3-hydroxypractolol.

Assay of prenalterol in plasma and urine by gas chromatography-mass spectrometry.

A sensitive and selective method for the quantitative analysis of prenalterol in plasma and urine is described. Prenalterol and the internal standard, deuterated prenalterol, are extracted with diethyl ether at pH 9.9 under salting-out conditions. Derivatization is performed by means of pentafluoropropionic anhydride in toluene before separation in the gas chromatograph. Detection and quantification of the triacyl derivatives are done by mass spectrometry in the selected ion monitoring mode. The method allows determination of concentrations down to 5 nmol/l (1 ng/ml) in 1 ml of sample, with a relative standard deviation below 10%.

The metabolic disposition of the selective beta 1-adrenoceptor agonist prenalterol in mice, rats, dogs, and humans.

The metabolic routes of the selective beta 1-adrenoceptor agonist prenalterol have been studied in mice, rats, dogs, and humans after oral administration. The drug was well absorbed from the gastrointestinal tract and most of the administered radioactivity was excreted in urine from all species within 24 hr. Prenalterol was metabolized to a varying extent in the species studied. About 20% of the 10-mg dose was recovered unchanged in man, the corresponding figures being 1.8% in the mouse, 7% in the rat, and 54% in the dog at 0.263 mg/kg (1 mumol/kg). Three metabolites were characterized and quantified by thin-layer chromatography, high-performance liquid chromatography, nuclear magnetic resonance (1H and 13C), and gas chromatography-mass spectrometry. Pronounced species variations in the metabolic pattern were observed. The phenolic sulfate ester of prenalterol was the main urinary metabolite in man, important in the dog, minor in the rat but not detectable in the mouse. Prenalterol glucuronide was formed in significant amounts in the animals and, in addition, beta-4(hydroxyphenoxy)lactic acid was present in dog urine. In the rat and the mouse the degree of biotransformation of prenalterol was significantly decreased at high oral doses of 2630 mg/kg (10 mmol/kg). The synthesis of prenalterol sulfate ester with use of ion pair extraction techniques is described.

Haemodynamic effects of prenalterol in patients on dialysis.

Haemodialysis hypotension occurs with particular frequency in bilateral nephrectomised patients. This reflects the importance of the renin-angiotensin-aldosterone system for maintaining normal blood pressure. Failure of vascular access (due to clotting and thrombosis of shunts) and ischaemic necrosis of transplanted kidneys in hypotensive patients prompted us to treat them orally with a new beta 1-adrenergic agent (prenalterol). Blood pressure was normalised in 4 out of 5 patients. Because of delayed renal elimination of the drug, daily dosage must be reduced to prevent symptoms of adrenergic stimulation. A study of the pharmacokinetics of prenalterol in uraemia is in preparation.

Determination of prenalterol in plasma and in urine by gas-liquid chromatography.

A description is given of a gas-liquid chromatographic method for the quantitative determination of unchanged prenalterol in plasma and for the total (free and conjugated) prenalterol in urine. After addition of an adequate internal standard, prenalterol together with the internal standard, is extracted with diethyl ether and derivatized with heptafluorobutyric anhydride-pyridine to form a tri-heptafluorobutyric derivative. This derivative has favourable properties for its estimation by gas-liquid chromatography using electron-capture detection. A large percentage of prenalterol is excreted as sulfate conjugate in man. Thus a hydrolysis step is added to the urine assay. The sensitivity of the method is about 2ng/ml.

Practolol metabolism in various small animal species.

1. The metabolism of the beta-adrenergic blocking agent practolol has been studied in a variety of small animal species, using both ring- and acetyl-14C-labelled material. After oral dosing at 100 mg/kg, elimination of 14C in urine and expired air was monitored, and urinary metabolite patterns were examined by t.l.c. 2. Marmoset was unusual in extensively deacetylating practolol (c. 57% dose). Urinary elimination was low, with only 25% being recovered in 4 days; over 30% of urinary 14C was present as desacetyl practolol, whereas less than 50% was unchanged practolol. 3. Hamster was also atypical, in its extensive hydroxylation of practolol. Urine contained 60% dose; 11% of urinary radioactivity was present as 3-hydroxypractolol, much of the polar material present (48%) appeared to be a conjugate of this, and only 35% was present as practolol. 4. For the other species studied (rat, mouse, guinea-pig and rabbit, metabolism was more limited. Deacetylation was typically about 5%, but was somewhat higher in the mouse (8--14%). Urine was the major route of elimination and practolol represented 50--90% of urinary radioactivity. 5. Despite extensive toxicity studies, both in species which metabolize practolol similarly to man and in species such as the hamster and marmoset which metabolize practolol extensively, no animal model has been found for the human adverse reactions.

Influence of the hemodialysis on the half-life of practolol in patients with severe renal failure.

Practolol, a recent and more selective beta-adrenergic receptor blocking drug, was given orally as a single dose of 200 mg to seven healthy volunteers and to six patients suffering from severe renal impairment and submitted to the long-term hemodialysis program. The plasma drug decay was markedly slowed and the plasma half-life was prolonged sixfold in the uremic patients in comparison to healthy volunteers. Hemodialysis (8 hours) starting 48 hours after drug intake lowered plasma practolol significantly but transiently. The shorter half-life during hemodialysis and the detection of equally high values of practolol in the ultrafiltrates as in the plasma demonstrate that this drug is readily removable from the plasma. However, the ascending slope of the plasma drug concentration curve which appeared following hemodialysis is suggestive of an incomplete drug removal from the body.

A study of practolol elimination in all grades of chronic renal failure.

Plasma and renal elimination of practolol have been studied in 12 patients with varying degrees of stable chronic renal failure and 14 normal volunteers. Each individual received 200 mg of oral practolol. The mean time to peak plasma level in the group of patients with renal failure was later than in the normal group, the difference between the two being significant. There were significant correlations between plasma practolol clearance and creatinine clearance, and also between renal practolol clearance and creatinine clearance. Total clearance of practolol from plasma was slightly higher than its renal clearance, the difference being significant, which suggested a small non-renal component to elimination. Renal practolol clearances tended to exceed creatinine clearances, the difference being significant, suggesting some renal tubular secretion of the drug. It is suggested that--in patients with chronic renal failure--the maintenance dose of practolol be reduced roughly in proportion to the reduction in creatinine clearance from normal. If effective plasma practolol concentrations are required quickly, the need for giving a loading dose becomes important under such circumstances.