ORAL ABSORPTION OF ANTI-ACQUIRED IMMUNE-DEFICIENCY SYNDROME NUCLEOSIDE ANALOGS .2. CARRIER-MEDIATED INTESTINAL TRANSPORT OF STAVUDINE IN RAT AND RABBIT PREPARATIONS

The intestinal transport and metabolism of stavudine (d4T), a nucleosi de analogue of thymidine used in the treatment of AIDS, was studied us ing single-pass intestinal perfusion (SPIP), intestinal brush-border m embrane vesicles (BBMV), and mucosal homogenates in rats and rabbits. In the SPIP, d4T demonstrated concentration-dependent mean wall permea bility (P(w)) at perfusate concentrations ranging from 0.001 to 25 mM . In coperfusion studies using 0.1 mM thymidine, 1 mM formycin B, or 5 mu M NBTI as putative inhibitors of d4T transport, the P(w) of 5 mu M d4T was reduced to 48%, 62%, and 70% of the control value, respectiv ely, suggesting the involvement of multiple nucleoside carriers in the intestinal uptake of d4T, d4T uptake in rat BBMV was significantly gr eater in the presence of a sodium ion gradient compared with a sodium- free (choline) gradient. The permeability of d4T, in the presence of a sodium gradient, was concentration-dependent and inhibited by 10 mM t hymidine but not significantly reduced by 10 mM formycin B. In the pre sence of 10 mu M NBTI, the permeability of d4T was not inhibited; howe ver, the binding of d4T to rat and rabbit BBMV was significantly reduc ed. Formycin B did not significantly reduce the d4T uptake in rat or r abbit BBMV suggesting that d4T does not interact with the purine-selec tive N1 nucleoside carrier. However, because formycin B inhibited d4T uptake in the SPIP and since d4T inhibited formycin B uptake in rat bu t not rabbit BBMV, it appears to interact with the N3 carrier which ha s been demonstrated in rat but not rabbit intestine. Also, an interact ion with the sodium-independent facilitative transporter at the basola teral membrane cannot be ruled out, The low hybrid K-m and high passiv e permeability of d4T likely account for the lack of saturable absorpt ion behavior observed in humans, whereas the brush-border and intracel lular stability of d4T preserve the high bioavailability observed afte r oral dosing.