Stable oral availability of sustained release propranolol when co‐ administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions.

Abstract

I A study was made of the influence of hydralazine on the oral availability of a sustained release formulation of propranolol (Inderal LA®). Sustained release propranolol 160 mg was given orally either alone or in combination with oral hydralazine 25 mg on separate occasions to six healthy volunteers. Blood and urine samples were collected post-dosing over 34 h. 2 Peak concentrations of propranolol, time to peak and area under the plasma concentration-time curve (AUC) were not altered by co-administration of hydralazine with sustained release propranolol. 3 Similarly, there was no change in recovery of '4C-labelled propranolol and metabolites in those individuals to whom tracer label was given. 4 These results contrast with previous reports of marked interaction between the conventional formulation of propranolol and hydralazine or food. 5 Interactions were confirmed between hydralazine and conventional propranolol in three subjects who had been studied previously with sustained release propranolol. Analysis of metabolite profiles in one of these subjects established that the major metabolites do change under hydralazine stimulus. 6 These results indicate that substrate delivery rates may determine presystemic drug interactions, suggesting capacity limitations of hydroxylation processes or short-term flow redistribution following hydralazine, resulting in functional shunting past the hydroxylation enzymes. 7 These results exclude global or lasting enzyme inhibition by hydralazine or simple flow-sensitivity of presystemic clearance.

Mechanisms and variations in the food effect on propranolol bioavailability

“…AUC of propranolol ng. h-ml ~ in the 7 subjects who participated both in the current and the previous study [ That the phenomenon was transient is also apparent from the fact that food did not enhance the bioavailability of propranolol given in a slow-release formulation [4,9]. A recent study on a propranolol-like compound, propafenone, showed that the extent of the food effect might depend upon the extent of oral clearance [15].…”

“…Rather, the increased bioavailability appeared to be secondary to a transient reduction in the hepatic extraction of propranolol. Such a reduction might be consequent to a transient increase in the hepatic delivery rate of the drug [5,8,9]. If the increase were sufficiently short-lived it could also help to explain why the increased availability of propranolol was not associated with a corresponding reduction in the total availability of any (oxidative) metabolite, but only with a delay (reduced AUC(0-60 min) in the appearance of one (NLA) or more of these metabolites.…”

“…On the other hand, food intake may reduce the presystemic conjugation of propranolol [4]. However, this need not result from inhibition of the conjugating enzyme, and it could hardly be the sole mechanism whereby food enhances the bioavailability of propranolol [4].The hepatic extraction of propranolol and hence the extent of its presystemic metabolism would be reduced if the rate of hepatic drug entry were increased [8,9]. Among the factors that may increase the rate of hepatic drug entry is the food-induced increase in the splanchnichepatic blood flow [5,7].…”

Influence of Food Intake on Presystemic Clearance of Drugs

“…Walle and co-workers suggested that the food-induced increase in propranolol bioavailability is proportional to the amount of protein in the meal (Walle et aI., 1981), but Mclean and coworkers reported similar increments after a predominantly carbohydrate stimulus and a high protein-lipid meal (Mclean et aI., 1981). Recent observations indicate that food does not reduce the presystemic clearance of propranolol when the drug is given in a slow-release formulation (Byrne et at, 1983). This is analogous to findings with hydralazine (Liedholm et aI., 1983) and is of considerable mechanistic interest (see section 5).…”

“…Specifically, it has been demonstrated that a transient increase in splanchnic-hepatic blood flow -as modelled on recorded food-drug interactions (Melander et al, 1977b) -could enhance the oral bioavailability of such drugs even if a flow-independent model of the liver itself were assumed (Mclean et al, 1978). In support of this model, 292 ingestion of the vasodilator hydralazine, which is known to enhance splanchnic-hepatic blood flow, has been found to increase the bioavailability of co-administered propranolol (Mclean et al, 1980), and administration of a slow-release formulation of propranolol ablated both the interaction associated with hydralazine and with food (Byrne et al, 1983). Furthermore, co-administration of the vasodilator glyceryl trinitrate and the high clearance drug dihydroergotamine gave a similar increase in dihydroergotamine bioavailability .…”