Mechanism and Site Dependency of Intestinal Mucosal Transport and Metabolism of Thymidine Analogues

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Abstract
This study has been undertaken to investigate the mechanisms of intestinal mucosal transport and metabolism of thymidine analogues and to identify any optimal site(s) of the rat intestine particularly involved in the absorption of thymidine analogues. The intestinal absorption of 3′-azido-3′-deoxythymidine (AZT) was studied at three initial concentrations in four segments of the rat intestine using an in situ recirculating perfusion technique. Disappearance of AZT followed first-order kinetics throughout the gastrointestinal (GI) tract at all tested concentrations. The apparent first-order rate constants were found to be relatively invariant over a broad range of concentrations from 0.01 to 1.0 mM. Corrected for the length of each segment, the apparent permeability (Papp) of AZT was 3.01 ± 0.32 × 10−5 cm/sec (mean ± SE) in the duodenum, 2.06 ± 0.24 × 10−5 cm/sec in the upper jejunum, 0.76 0.13 × 10−5 cm/sec in the combined lower jejunum and ileum, and 0.32 ± 0.10 × 10−5 cm/sec in the colon, which indicated that intrinsic absorptivity was greater in the upper GI tract than in the lower portions possibly due to the differences in surface area for absorption. No AZT metabolite appeared in any part of the GI tract. On the other hand, thymidine and other analogues, i.e., 5-iodo-2′-deoxyuridine and 2′-deoxyuridine, were rapidly metabolized into nucleobase and sugar in the upper GI tract, whereas in the colon no metabolite appeared. A free 3′-OH group appears to be necessary for the metabolism (catabolism) of thymidine analogues in the rat intestine mainly by pyrimidine nu-cleoside phosphorylase. Finally, bile salt-acylcarnitine mixed micelles appeared to be an effective adjuvant in promoting colonic absorptions of AZT and phenol red. The use of mixed micelles increased the apparent permeabilities of AZT in the colon by a factor of 5.4, and for phenol red the permeability increased from a negligible value to 1.76 × 10−5 cm/sec. Since the absorptions of both AZT and phenol red were enhanced by mixed micelles, a paracel-lular transport pathway may be involved.