title: Inactivation of the intestinal uptake system for beta-lactam antibiotics by diethylpyrocarbonate.
abstract: The uptake system for beta-lactam antibiotics in the rabbit small intestine was investigated using brush-border membrane vesicles. After treatment of membrane vesicles with the reagent diethylpyrocarbonate (DEP), the uptake of orally active beta-lactam antibiotics with an alpha-amino group in the substituent at position 6 or 7 of the penam or cephem nucleus was significantly inhibited, whereas DEP-treatment had no inhibitory effect on the uptake of beta-lactam antibiotics without an alpha-amino group. The kinetic analysis revealed an apparent competitive inhibition indicating a decreased affinity of the transport system for alpha-amino-beta-lactam antibiotics. Substrates of the intestinal dipeptide transport system - dipeptides and alpha-amino-beta-lactam antibiotics - could protect the transport system from irreversible inhibition by DEP, whereas beta-lactam antibiotics without an alpha-amino group as well as amino acids or bile acids had no effect. Incubation of DEP-treated vesicles with hydroxylamine led to a partial restoration of the transport activity indicating that DEP may have led to a modification of a histidine residue of the transport protein. From the data presented we conclude that a specific interaction of the alpha-amino group in the substituent at position 6 or 7 of the penam or cephem nucleus presumably with a histidine residue of the transport protein is involved in the translocation process of orally active alpha-amino-beta-lactam antibiotics across the intestinal brush-border membrane.
authors.affiliation: Hoechst Aktiengesellschaft, Frankfurt am Main, F.R.G.
authors.forename: W
authors.initials: W
authors.lastname: Kramer
authors.forename: F
authors.initials: F
authors.lastname: Girbig
authors.forename: E
authors.initials: E
authors.lastname: Petzoldt
authors.forename: I
authors.initials: I
authors.lastname: Leipe
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002506:Cephalexin / Q000378:metabolism; D002511:Cephalosporins / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004047:Diethyl Pyrocarbonate / Q000494:pharmacology*; D005561:Formates / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D019811:Hydroxylamine; D006898:Hydroxylamines / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D010406:Penicillins / Q000378:metabolism; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D005561:Formates; D006898:Hydroxylamines; D010406:Penicillins; D019811:Hydroxylamine; D004047:Diethyl Pyrocarbonate; D002506:Cephalexin