title: The effect of protein binding and lipophilicity of penicillins on their in-vitro flux across gastric mucosa.
abstract: Delivery of amoxycillin across the human gastric mucosa to Helicobacter pylori is poor compared with that of metronidazole and clarithromycin, limiting the clinical effectiveness of this penicillin. To investigate the physicochemical properties of penicillins that influence their flux across gastric mucosa, the fluxes of metronidazole and eight penicillins were measured in vitro across rat gastric mucosa. The lipophilicity of these drugs was also measured using potentiometric titration. The mean fluxes of monobasic penicillins (range 0.66-0.89 nmol/cm2/h) were significantly lower than those of the aminopenicillins (range 1.94-2.80 nmol/cm2/h) (P < 0.005). Penicillin flux was not significantly correlated with lipophilicity as measured, but was significantly correlated with published protein binding data (rs = 0.9048, P < 0.002). Metronidazole flux was significantly higher than that of any penicillin at 22.6 (+/-0.9) nmol/cm2/h (P < 0.001). Therefore, the in-vitro gastric delivery of penicillins can be predicted from protein binding which may in turn predict activity against H. pylori in vivo.
authors.affiliation: Division of Gastroenterology, University Hospital, Nottingham, UK.
authors.forename: A F
authors.initials: AF
authors.lastname: Goddard
authors.forename: P O
authors.initials: PO
authors.lastname: Erah
authors.forename: D A
authors.initials: DA
authors.lastname: Barrett
authors.forename: P N
authors.initials: PN
authors.lastname: Shaw
authors.forename: R C
authors.initials: RC
authors.lastname: Spiller
mesh_terms: D000818:Animals; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D008795:Metronidazole / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D010406:Penicillins / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D010406:Penicillins; D011506:Proteins; D008795:Metronidazole