In vivo half life

Litde is known about metaboHc inactivation of ( -endorphin and the dynorphins. NEP, and to a lesser extent APN, are only weaMy active against P-endorphin (183). Enzymes are known which degrade P-endorphin in vitro under nonphysiological conditions (202) or which inactivate P-endorphin by N-acetjlation (203). Alack of specific degradative enzymes for these peptides may account for their relatively long half-life in vivo though this has not been definitively estabUshed. 

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

SMPT often is used in place of SPDP for the preparation of immunotoxin conjugates. The hindered disulfide of SMPT has distinct advantages in this regard. Thorpe et al. (1987) showed that SMPT conjugates had approximately twice the half-life in vivo as SPDP conjugates. Antibody-toxin conjugates prepared with SMPT possess a half-life in vivo of up to 22 hours, presumably due to the decreased susceptibility of the hindered disulfide toward reductive cleavage. 

Resistance to peptidases was also reported for the octapeptoid 6.106 when incubated with papain, chymotrypsin, or thermolysin [229], However, resistance to peptidases may not be synonymous with a long half-life in vivo, since many factors beside peptidases can be expected to contribute to the elimination of peptoids. An indirect indication of this effect can be found for antimicrobial peptoids and particularly compound CHIR29498 (6.107) [232], In mice infected with Staphyllococus aureus, this peptoid was less active when injected 2 h post-infection compared to 0 h or 0.5 h. The conclusion drawn by the authors was that the compound requires optimization for improved absorption or stability within the body. 

Systematic modification of the octapeptide sequence from cin-giotensinogen (Figure 1) was undertaken to incorporate desirable properties into the peptide. Addition of a prolyl residue to the N-termlnus Improved solubility at physiologic pH, replacement of the leucyl-leucine sequence with phenylalanyl residues Improved inhibitory properties by forty-fold, and addition of a lysyl residue to the C-termlnus Increased solubility and extended half-life in vivo. These modifications yielded the Renin Inhibitory Peptide TriP) vdiich effectively blocks renin both in primates (11) and man (1 2). 

Lau, D., Kuzma, G., Wei, C-M., Livingston, D.J., and Hsiung, N. (1987). A modified human tissue plasminogen activator with extended half-life in vivo. Bio/Technology 5,953 958. 

The measurement of BAP has several advantages over osteocalcin measurement. Because of its relatively long half-life in vivo (1 to 3 days), it is relatively unaffected by diurnal variation. BAP is more stable in vitro and does not require special specimen handling. BAP is more useful in individuals with impaired renal function because it is not cleared by glomerular filtration. 

A major problem in aU drug discovery programs is to discover compounds with good pharmacokinetics. Although it is possible to examine the metabolism of the drug in animals, it has often been difficult to predict what would happen in man. The obvious implications of drug metabolism are an effect on half-life in vivo and the production of toxic metabolic products. 

Organochlorine pesticides include aldrin, chlordane, dichophane (DDT), dieldrin (also a metabolite of aldrin) endrin heptachlor, hexachlorobenzene (EICB), 1, 2, 3, 4, 5, 6-hexachlorocyclohexane (EICEI = benzenehexachloride, BE1C), and lindane (gamma - EICEI). These compounds were widely used but persist in the environment, and lindane, which has a relatively short half-life in vivo, is now the only member of this group still in common use. Pentachlorophenol is used as a contact herbicide. This compound is still widely used in wood preservatives and disinfectants. 

An ideal fibrinolytic medicine should have the following properties [62] (1) Strong fibrinolytic activity (2) Specificity on fibrinogen and fibrin (3) Low immunogenicity (4) Long half-life in vivo, (5) Low re-occlusion rate and (6) Reasonable cost. 

Compound 69c was proved to maintain good activity in vitro but had a short half-life in vivo due to hydroxylation of the 4"-side chain by cytochome P-450 followed by conversion to CP-418,001 (69d), which was inactive. To avoid such metabolism, a methyl group was introduced to the a-side chain of 69c to obtain CP-416,890 (69e). It exhibited increased stability to metabolism and good in vivo activity. Finally, synthesized 69f, which bears a smaller side chain, demonstrated superior in vitro and in vivo activity, particularly against S. pneumoniae, including the MLS-i and mef type of resistant strains. Its pharmacokinetic profile is comparable to AZM (19) and telithromycin (TLM) (91i) [87-93]. However, the antibacterial activity of 69f seems to be insufficient against MLS-c resistant strains of S. pneumoniae and H. influenzae compared with 91i and ABT-773 (95) (Schemes 8 and 11). 

---