Permeability of a novel beta-lactamase inhibitor LK-157 and its ester prodrugs across rat jejunum in vitro.
OBJECTIVE
LK-157 is a novel 10-ethylidene tricyclic carbapenem that resembles the structure of the broad-spectrum antibiotic sanfetrinem and acts as a potent inactivator of beta-lactamases of classes A, C and D. LK-157 is a highly soluble but poorly permeable drug. Since most of the beta-lactams are poorly absorbed, ester prodrugs LK-159, LK-157E1 and LK-157E2 were designed to enhance membrane permeability. This study investigated the permeability of LK-157 and the three ester prodrugs across rat intestine in vitro. The morpholinoethyl ester of sanfetrinem was also investigated.


METHODS
Permeability across rat jejunum was determined using EasyMount side-by-side diffusion chambers.


RESULTS
The solubility and permeability of morpholinoethyl ester LK-157E2 were superior to those of LK-159 and LK-157E1. The morpholinoethyl ester of sanfetrinem LK-176E1 had the highest observed permeability coefficient and consequently the highest predicted absorption in humans.


CONCLUSIONS
These results suggest that the morpholinoethyl esters of LK-157 and sanfetrinem could be further investigated to assess bioavailability in vivo.
Iglicar
Petra
P
Lek Pharmaceuticals d.d., Verovskova 57, Ljubljana Sl-1526, Slovenia. petra.iglicar@sandoz.com
Legen
Igor
I
Vilfan
Gregor
G
Selic
Lovro
L
Prezelj
Andrej
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D015780:Carbapenems / Q000737:chemistry / Q000493:pharmacokinetics*; D004952:Esters / Q000737:chemistry / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007583:Jejunum / Q000378:metabolism*; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D004952:Esters; C539935:LK-157; D007769:Lactams; D009025:Morpholines; D011355:Prodrugs; D012997:Solvents; D013501:Surface-Active Agents; D065093:beta-Lactamase Inhibitors; C544419:morpholinoethyl 10-(1-hydroxyethyl)-4-methoxy-11-oxoazatricyclo(7.2.0.0(3,8))undec-2-encarboxylate; C104757:sanfetrinem