Stability of cephalosporin prodrug esters in human intestinal juice: Implications for oral bioavailability
Stability of cephalosporin prodrug esters in human intestinal juice: Implications for oral bioavailability
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DOI：
10.1128/aac.42.10.2602
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发表时间：
1998-10-01
影响因子：
4.9
通讯作者：
Blouin, RA
中科院分区：
文献类型：
--
作者：
Stoeckel, K;Hofheinz, W;Blouin, RA
本文比较了头孢他美酯（CAT）、头孢呋辛酯（CAE）和头孢泊肟酯（CPD）在0.6M磷酸盐缓冲液（pH7.4）和人肠液（pH7.4）中于37 ℃ 24小时内的降解程度。(i)Delta 2-和Delta 3-头孢菌素的相对比例在两种孵育培养基中大致相反。在磷酸盐缓冲液中，主要降解产物是Delta 2-头孢菌素（CAT = 61%：CAE = 74%; CPD = 85%）。肠液中以Delta 3-头孢菌素为主（CAT = 86%，CAE = 75%，CPD = 87%）。(ii)通常，前药酯的降解在肠液中比在磷酸盐缓冲液中进行得更快（例如，对于CAT，半衰期[t（1/2）s]分别为0.78和4.3 h）。(iii)CAE和CPD的HCO非对映异构体在肠液中以不同的速率降解（对于CAE非对映异构体，t（1/2）s = 0.37和0.93 h;对于CPD非对映异构体，t（1/2）s = 0.18和0.98 h），但在磷酸盐缓冲液中以相似速率降解（对于CAE非对映异构体，t（1/2）= 1.6 h;对于CPD，t（1/2）非对映异构体。结论是（i）Δ 2异构化不显著影响前药酯的生物利用度，因为在肠液中的酶促水解主要进行活性Δ 3-头孢菌素和（II）酶促酯水解的高度立体选择性应使得可能增加某些前药酯的生物利用度（CAE，CPD）通过使用更稳定的二异丙基异构体。
The levels of degradation of cefetamet pivoxil (CAT), cefuroxime axetil (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 relative proportions of the Delta 2- and Delta 3-cephalosporins ,were roughly reversed in the two incubation media. In phosphate buffer, the major degradation product was the Delta 2-cephalosporin (CAT = 61%: CAE = 74%; CPD = 85%). while in intestinal juice it was the Delta 3-cephalosporin (CAT = 86%; CAE = 75%; CPD = 87%). (ii) Generally, the degradation 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 CPD were degraded at different rates in intestinal juice (for the CAE diastereoisomers, t(1/2)s = 0.37 and 0.93 h; for the CPD diastereoisomers, t(1/2)s = 0.18 and 0.98 h) but were degraded at similar rates in phosphate 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 Delta 2 isomerization does not significantly affect the bioavailability of prodrug esters since enzymatic hydrolysis in the intestinal fluid proceeds mainly to the active Delta 3-cephalosporin and (II) the high degree of stereoselectivity of the enzymatic ester hydrolysis should make it possible to increase the bioavailabilities of certain prodrug esters (CAE, CPD) by using the more stable diasterioisomer.