First Pass Hydroxylation of Nortriptyline: Concentrations of Parent Drug and Major Metabolites in Plasma

Nortriptyline was given orally and intramuscularly to six depressed patients. Plasma concentrations of parent drug and the unconjugated and conjugated principal metabolite, 10-hydroxynortriptyline, were determined by mass fragmentography. There was a significant decrease in the area under the nortriptyling plasma concentration- time curve after the oral route of administration, whilst the elimination rate was unchanged. With the oral dose, plasma concentrations of the metabolites were higher and peaked earlier than after intramuscular administration, whilst the opposite was true for the parent compound. This proves that the difference in bioavailability between the two routes of administration was due to first pass metabolism. As determined from the ratio between corresponding areas, the relative bioavailability of the oral dose was 66 +-21 S.D. per cent. This fraction is higher than that reported previously when intravenous nortriptyline was used as the reference dosage form.