Anticoagulant activity of a peptide boronic acid thrombin inhibitor by various routes of administration in rats.
The peptide boronic acid analog Ac-(D)Phe-Pro-boroArg-OH (I) is a potent and selective inhibitor of thrombin. The objective of this study was to determine whether I is active orally or when administered by alternative transmucosal routes. The measured effect was the time for clotting of plasma after initiation with thrombin. With this assay there was a narrow window from no measurable effect to the maximal effect, a clotting time greater than 300 seconds. Intravenous I at a 0.15 mg/kg dose in rats, a nasal 0.45 mg/kg dose, and 3 mg/kg doses administered orally, colonically, or rectally all produced maximal effects. Therefore, although bioavailability cannot be estimated, it is demonstrated that this peptide analog was absorbed by each of these routes.
Hussain
M A
MA
DuPont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
Knabb
R
R
Aungst
B J
BJ
Kettner
C
C
D000281:Administration, Intranasal; D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001896:Boron Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D003106:Colon; D004333:Drug Administration Routes; D007275:Injections, Intravenous; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012007:Rectum; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D001896:Boron Compounds; D009842:Oligopeptides; C066061:acetylphenylalanyl-prolyl-boroarginine; D013917:Thrombin