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Pharm Res
2012 Apr 01;294:1134-42. doi: 10.1007/s11095-012-0673-0.
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Rectal absorption of vigabatrin, a substrate of the proton coupled amino acid transporter (PAT1, Slc36a1), in rats.
Holm R
,
Kall MA
,
Frølund S
,
Nielsen AL
,
Jensen A
,
Broberg ML
,
Nielsen CU
.
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To investigate the rectal absorption of vigabatrin in rats, based on the hypothesis that PAT1 (Slc36a1) is involved. Male Sprague-Dawley rats were dosed rectally with five different gels, varying in buffer capacity, the amount of vigabatrin, and co-administration of proline or tryptophan. Western blotting was used to detect rPAT1 in rat rectal epithelium. X. Laevis oocytes were injected with SLC36A1 cRNA for the expression of hPAT1, prior to two-electrode voltage clamp measurements. rPAT1 protein was present in rat rectal epithelium. Approximately 7%-9% of a 1 mg/kg vigabatrin dose was absorbed after rectal administration, regardless of the formulation used. Increasing the dose of vigabatrin 10-fold decreased the absolute bioavailability to 4.2%. Co-administration of proline or tryptophan changed the pharmacokinetic profile, indicating a role of PAT1 in the rectal absorption of vigabatrin. Transport of vigabatrin via hPAT1 expressed in X. Laevis oocytes had a K(m) of 5.2 ± 0.6 mM and was almost completely inhibited by tryptophan. Although vigabatrin is a PAT1 substrate and the rPAT1 protein is expressed in the rectumepithelium, vigabatrin has low rectal absorption in rats.
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