Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter.

Article Details

Citation

Menter A, Thrash B, Cherian C, Matherly LH, Wang L, Gangjee A, Morgan JR, Maeda DY, Schuler AD, Kahn SJ, Zebala JA

Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter.

J Pharmacol Exp Ther. 2012 Sep;342(3):696-708. doi: 10.1124/jpet.112.195479. Epub 2012 May 31.

PubMed ID
22653877 [ View in PubMed
]
Abstract

N-[4-[[(2,4-diamino-6-pterdinyl)methyl]amino]benzoyl]-L/D-glutamic acid (L/D-AMT) is an investigational drug in phase 1 clinical development that consists of the L-and D-enantiomers of aminopterin (AMT). L/D-AMT is obtained from a novel process for making the L-enantiomer (L-AMT), a potent oral antiinflammatory agent. The purpose of these studies was to characterize oral uptake and safety in the dog and human of each enantiomer alone and in combination and provide in vitro evidence for a mechanism of intestinal absorption. This is the first report of L /D-AMT in humans. In dogs (n = 40) orally dosed with L-AMT or D-AMT absorption was stereoselective for the L-enantiomer (6- to 12-fold larger peak plasma concentration after oral administration and area under the plasma concentration-time curve at 0-4 h; p < 0.001). D-AMT was not toxic at the maximal dose tested (82.5 mg/kg), which was 100-fold larger than the maximal nonlethal L-AMT dose (0.8 mg/kg). Dogs (n = 10) and humans with psoriasis (n = 21) orally administered L-AMT and L /D-AMT at the same L-enantiomer dose resulted in stereoselective absorption (absent D-enantiomer in plasma), bioequivalent L-enantiomer pharmacokinetics, and equivalent safety. Thus, the D-enantiomer in L/D-AMT did not perturb L-enantiomer absorption or alter the safety of L-AMT. In vitro uptake by the human proton-coupled folate transporter (PCFT) demonstrated minimal transport of D-AMT compared with L-AMT, mirroring the in vivo findings. Enantiomer selectivity by PCFT was attributable almost entirely to decreased binding affinity rather than changes in transport rate. Collectively, our results demonstrate a strong in vitro-in vivo correlation implicating stereoselective transport by PCFT as the mechanism underlying stereoselective absorption observed in vivo.

DrugBank Data that Cites this Article

Drugs
Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AminopterinProton-coupled folate transporterProteinHumans
Unknown
Not AvailableDetails