STABILITY OF CEPHALOSPORIN PRODRUG ESTERS IN HUMAN INTESTINAL JUICE -IMPLICATIONS FOR ORAL BIOAVAILABILITY

The levels of degradation of cefetamet pivoxil (CAT), cefuroxime axeti l (CAE), and cefpodoxime proxetil (CPD) in 0.6 M phosphate buffer (pH 7.4) and human intestinal juice (pH 7.4) at 37 degrees C over 24h were compared, Significant differences in the time courses of degradation and in the patterns of degradation products were observed. (i) The rel ative proportions of the Delta 2- and Delta 3-cephalosporins ,were rou ghly reversed in the two incubation media. In phosphate buffer, the ma jor degradation product was the Delta 2-cephalosporin (CAT = 61%: CAE = 74%; CPD = 85%). while in intestinal juice it was the Delta 3-cephal osporin (CAT = 86%; CAE = 75%; CPD = 87%). (ii) Generally, the degrada tion of the prodrug esters progressed faster in intestinal juice than in phosphate buffer (e.g., for CAT the half-lives [t(1/2)s] were 0.78 and 4.3 h, respectively). (iii) The hco diastereoisomers of CAE and CP D were degraded at different rates in intestinal juice (for the CAE di astereoisomers, t(1/2)s = 0.37 and 0.93 h; for the CPD diastereoisomer s, t(1/2)s = 0.18 and 0.98 h) but were degraded at similar rates in ph osphate buffer (for the CAE diastereoisomers, t(1/2) = 1.6 h; for the CPD t(1/2) diastereoisomers. = 2.2 h), It is concluded that (i) the De lta 2 isomerization does not significantly affect the bioavailability of prodrug eaters since enzymatic hydrolysis in the intestinal fluid p roceeds mainly to the active Delta 3-cephalosporin and (II) the high d egree of stereoselectivity of the enzymatic ester hydrolysis should ma ke it possible to increase the bioavailabilities of certain prodrug es ters (CAE, CPD) by using the more stable diasterioisomer.