Purpose: Since the ability of the small intestine to biotransform a drug may decrease in distal segments of the intestine, this study aimed to assess whether the site of administration in the small intestine could affect the systemic bioavailability of diltiazem and its two active metabolites, N-desmethyldiltiazem (MA) and desacetyl-diltiazem (M1).
Methods: Five mg/kg of diltiazem were administered into the lumen of the proximal (0-30 cm, n = 9) or the distal (150-180 cm) small intestine (n = 7) of anesthetized New Zealand rabbits. Blood samples were drawn from the femoral artery for 6 hours, and diltiazem, MA and M1 were assayed by HPLC.
Results: The area under the curve (AUC0-->infinity) of diltiazem administered into the distal small intestine was larger than that estimated when diltiazem was given in the proximal segment (14.20 +/- 2.82 vs 8.14 +/- 0.88 micrograms.min/ml, p < 0.05), due to a lower diltiazem oral clearance (440 +/- 78 vs 660 +/- 55 ml/min/kg, p < 0.05). The AUC0-->360 of MA was not affected by the site of diltiazem administration, but the AUC0-->360 of M1 was increased when diltiazem was administered in the distal segment of the small intestine. When administered into the distal segment of the intestine, the molar sum of diltiazem and its active metabolites was 48% greater than when delivered into the 0-30 cm segment of the small intestine; as a consequence, absorption of diltiazem in distal segments of the small intestine may enhance its pharmacological response.
Conclusions: The site of absorption into the intestine modulates the bioavailability of diltiazem and its two active metabolites.