Kinetics and pattern of degradation of thyrotropin-releasing hormone (TRH) in human plasma.
The kinetics and mechanism of degradation of the tripeptide TRH (pGlu-His-Pro-NH2) and its various primary and secondary degradation products (TRH-OH, His-Pro-NH2, and His-Pro) have been determined in human plasma at 37 degrees C. The rates of degradation of both TRH and TRH-OH (pGlu-His-Pro) showed mixed zero-order and first-order kinetics. At low substrate concentrations first-order kinetics occurred, with TRH and TRH-OH degradation half-lives of 9.4 and 27 min, respectively. The initial step in the plasma-catalyzed degradation of TRH is due to hydrolysis of the pGlu-His bond by the TRH-specific pyroglutamyl aminopeptidase serum enzyme, resulting in the exclusive formation of histidyl-proline amide (His-Pro-NH2). Using specific HPLC methods the major degradation route (67%) of this dipeptide in human plasma was hydrolysis of the peptide bond to yield His and Pro-NH2, whereas deamidation to yield His-Pro accounted for 29% of the total degradation. A minor pathway (less than or equal to 4%) was spontaneous cyclization to yield cyclo(His-Pro). Both His-Pro-NH2 and His-Pro degraded by first-order kinetics and faster than TRH, with half-lives of 5.3 and 2.2 min, respectively, in 80% plasma.
Møss
J
J
Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen, Denmark.
Bundgaard
H
H
D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D010276:Parasympatholytics / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000097:blood* / Q000493:pharmacokinetics
D010276:Parasympatholytics; C020271:thyrotropin-releasing hormone, deamido-; D013973:Thyrotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid