Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach.
A prodrug strategy was applied to guanidino-containing analogues to increase oral absorption via hPEPT1 and hVACVase. l-Valine, l-isoleucine, and l-phenylalanine esters of [3-(hydroxymethyl)phenyl]guanidine (3-HPG) were synthesized and evaluated for transport and activation. In HeLa/hPEPT1 cells, Val-3-HPG and Ile-3-HPG exhibited high affinity to hPEPT1 (IC(50): 0.65 and 0.63 mM, respectively), and all three l-amino acid esters showed higher uptake (2.6- to 9-fold) than the parent compound 3-HPG. Val-3-HPG and Ile-3-HPG demonstrated remarkable Caco-2 permeability enhancement, and Val-3-HPG exhibited comparable permeability to valacyclovir. In rat perfusion studies, Val-3-HPG and Ile-3-HPG permeabilities were significantly higher than 3-HPG and exceeded/matched the high-permeability standard metoprolol, respectively. All the l-amino acid 3-HPG esters were effectively activated in HeLa and Caco-2 cell homogenates and were found to be good substrates of hVACVase (k(cat)/K(m) in mM(-1) x s(-1): Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660). In conclusion, a prodrug strategy is effective at increasing the intestinal permeability of polar guanidino analogues via targeting hPEPT1 for transport and hVACVase for activation.
Sun
Jing
J
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA.
Dahan
Arik
A
Amidon
Gordon L
GL
D000596:Amino Acids / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004952:Esters / Q000737:chemistry; D006146:Guanidines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006367:HeLa Cells; D006801:Humans; D007408:Intestinal Absorption; D007700:Kinetics; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000493:pharmacokinetics*; D027981:Symporters / Q000378:metabolism
D000596:Amino Acids; D000998:Antiviral Agents; D004952:Esters; D006146:Guanidines; D000074011:Peptide Transporter 1; D011355:Prodrugs; C082186:SLC15A1 protein, human; D027981:Symporters; C026943:phenylguanidine; C093745:BPHL protein, human; D002265:Carboxylic Ester Hydrolases