P44.12 LB
Background: Cell culture models for studying drug disposition and drug-drug interactions are good but they cannot reflect the heterogeneous cellular coexistence typical of colo-rectal mucosa. The aim of this study was to establish an ex vivo excised tissue model which is closer to the more complex in vivo situation and apply it for studying the transport and interactions of darunavir (DRV) with other ARVs as reports suggest that combination microbicides is more effective.
Methods: Colo-rectal tissue from a male New Zealand white rabbit was excised and transferred to oxygenated ice cold Kreb's buffer. A strip of the colo-rectal segment was opened with a lateral cut thus making a planar sheet, rinsed free of luminal contents with Kreb's buffer and stripped of the muscle layers before being mounted between two-diffusion half-cells containing oxygenated transport buffer solutions. The permeability of darunavir was measured; interactions with transporter inhibitor elacridar and effect of co-administration with tenofovir were evaluated in 3 independent experiments.
Results: The respective absorptive and secretory permeability of DRV across rabbit colo-rectal mucosa was 1.8 ± 2.2 × 10−6 cm/s and 4.6 ± 3.1 × 10−6 cm/s (ER-efflux ratio 3). Modulation of the transport of DRV (10 μM) by elacidar (1 μM) showed that absorptive transport increased by 4.4 fold and secretory transport decreased by 0.3 fold (ER 0.2). Co-administration of TFV (100 μM), with DRV resulted in 1.6 fold increase in absorptive direction and 0.5 fold decrease in secretory direction as compared to the transport of singlet agent (ER 0.8).
Conclusions: Transport of DRV was vectorial and affected by transporter inhibitors, suggesting that DRV is a substrate of P-glycoprotein. DRV transport was affected by the presence of tenofovir. The intact colo-rectal tissue model is a valuable technique and this could be extended to include excised tissue samples from non-human primates as well as applied for assessing cervico-vaginal drug transport.
