Bioavailability kinetics, after oral administration

Phenoxybenzamine is absorbed after oral administration, although bioavailability is low and its kinetic properties are not well known. The drug is usually given orally, starting with low doses of 10-20 mg/d and progressively increasing the dose until the desired effect is achieved. Less than 100 mg/d is usually sufficient to achieve adequate -receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below). 

The AUCs can be obtained by administration of intravenous and oral formulations in a crossover study. It is important to use the exact dose rather than nominal doses the oral and intravenous formulations should be assayed, and the syringes or giving sets used for the intravenous administration carefully weighed before and after dosing. The size of the intravenous dose should be reduced compared with the oral dose in proportion to the expected bioavailability so that the AUCs will be similar. This avoids assumptions about linear kinetics and maximises safety, since high plasma concentrations by the intravenous route are avoided. Similarly, it is appropriate to infuse the intravenous drug over a period comparable with the time to maximum concentration (T j g ) after oral administration in order to avoid transient high peaks. 

The data from the above studies provide the basis for a better understanding of the disposition of APs in fish. They show that oral administration or waterborne exposure results in an efficient uptake of these chemicals. Radiolabeled NPs are rapidly absorbed from the gastrointestinal tract, as demonstrated by the radioactivity levels detected in blood and tissues 24 h after dosing. It is difficult to determine precisely the oral bioavailability of these compounds on the basis of the published studies. Nevertheless, Thibaut et al.6S 69 reported that 48 h after the administration of 3H-4-h-NP to rainbow trout, 5.5 and 3.0% of the radioactivity was recovered from bile and urine, respectively. This suggests that the digestive absorption must be at least 8.5%. Nevertheless, very little information is available on the kinetics of residues in fish submitted to a repeated AP oral exposure. 

If an intravenous formulation can be developed, a crossover absolute bioavailability study in healthy volunteers can provide an unambiguous measure of clearance and volume of distribution as well as absolute bioavailability and absorption kinetics of the clinical formulation. Comparison of metabolite pharmacokinetics after oral and intravenous administration can provide information on first-pass metabolism. 

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