Kinetic analysis of dehydropeptidase-I and comparative in vitro and in vivo stabilities of PS-5 derivatives modified at the C-3 side chain.
With partially purified kidney dehydropeptidase-I (DHP-I) preparations, the hydrolysis kinetics of glycyldehydrophenylalanine (Gly-dPh) by DHP-I were found to be completely non-Michaelian, whereas those of PS-5 and imipenem were composed of at least two-phase reactions which were also observed using Bacillus cereus type II beta-lactamase. Thus the DHP-I stabilities of 34 PS-5 carbapenem derivatives which were synthesized by chemical modification at the C-3 side chain of PS-5 were examined in vitro using fresh mouse, dog and human DHP-I preparations, and are tentatively expressed in reference to the DHP-I stabilities of PS-5. The in vitro DHP-I stability of PS-5 was significantly improved by introduction of basic side chains and cysteines at C-3. More particularly, the D-cysteinyl side chain was more stable relative to DHP-I than the L-cysteinyl. In vivo, however, the degree of improvement of the DHP-I-stability by chemical modification at C-3 was not sufficient enough to establish therapeutically effective levels of serum concentrations and urinary recoveries of the carbapenem derivatives after parenteral administration.
Sakamoto
M
M
MERCIAN Corporation, Central Research Laboratories, Fujisawa, Japan.
Yamamoto
K
K
Isshiki
K
K
Tone
H
H
Ishikura
T
T
Fukagawa
Y
Y
Yoshioka
T
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015780:Carbapenems / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004150:Dipeptidases / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008252:Macaca fascicularis; D051379:Mice; D013552:Swine; D013845:Thienamycins / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; C016883:PS 5; D004150:Dipeptidases; C038937:dipeptidase