Pharmacokinetics of trefoil peptides and their stability in gastrointestinal contents.
Trefoil factor family (TFF) peptides are considered promising for therapeutic use in gastrointestinal diseases, and there is a need to explore the fate of injected TFF and the stability of the peptides in the gastrointestinal tract. We studied the pharmacokinetics of intravenously (i.v.) administered hTFF2 in mice and rats and of hTFF3 administered i.v., intramuscularly, intraperitoneally, and subcutaneously in mice, and estimated by ELISA the decay of the peptides added to rat and human gastrointestinal contents. We found that i.v. injected hTFF2 and hTFF3 were cleared from the circulation within 2-3h, exhibiting comparable pharmacokinetic profiles. In contents from the rat stomach, hTFF levels remained unchanged for up to 6 days. In the small and large intestine of rats, the hTFF levels decreased markedly after 4 and 1h, respectively. In small intestinal contents from humans, the levels remained stable for more than 24h. We conclude that systemically administered hTFF2 and hTFF3 are rapidly eliminated from the circulation and that the stability of hTFF2 and hTFF3 in GI contents appeared higher in the gastric and small intestinal milieu than in the large intestine and feces, suggesting a higher stability toward gastric acid and digestive enzymes than toward microbial degradation.
Kjellev
Stine
S
Immunopharmacology, Novo Nordisk a/s, DK-2760 Maaloev, Denmark. skje@novonordisk.com
Vestergaard
Else Marie
EM
Nexø
Ebba
E
Thygesen
Peter
P
Eghøj
Maria S
MS
Jeppesen
Palle B
PB
Thim
Lars
L
Pedersen
Nis Borbye
NB
Poulsen
Steen Seier
SS
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005243:Feces / Q000737:chemistry; D005260:Female; D005766:Gastrointestinal Contents / Q000187:drug effects*; D006801:Humans; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D000071164:Trefoil Factor-2
D010455:Peptides; D000071164:Trefoil Factor-2