PHARMACOKINETICS OF PAFENOLOL IN THE RAT - A SUITABLE MODEL FOR STUDYING ABSORPTION MECHANISMS OF A DRUG EXHIBITING UNUSUAL ABSORPTION PROPERTIES IN MAN

The pharmacokinetics of pafenolol, a highly selective β1‐adrenoceptor antagonist, have been studied in starved and unstarved rats. Separate groups received intravenous doses (0·3 and 3·0 μmol kg−1) and oral doses (1 and 25 μmol kg−1). The systemic clearance of pafenolol was constant in the dose range investigated where the absolute oral bioavailability increased from 15 to 27 per cent in the starved and from 9·1 to 21 per cent in the unstarved rats, when the oral dose was raised from 1 to 25 μmol kg−1. The blood concentration profile after an oral solution of pafenolol exhibited two peaks in the majority of the rats. The major part of the absorption was associated with the second peak which appeared about 4 h after dosing in both starved and unstarved rats. Food lowered the degree of bioavailability and shifted the t max 1, to about 1 hour compared to half an hour in starved rats. The low bioavailability was primarily due to incomplete uptake from the gastrointestinal tract. Our study shows that pafenolol is absorbed in a similar way to that in man. The mechanisms behind the dose‐dependent bioavailability and the two peaks in the absorption profile after an oral solution will be further explained in the rat. Copyright © 1990 John Wiley & Sons, Ltd.