Isomerization of Cephalosporin Esters: Implications for the Prodrug Ester Approach to Enhancing the Oral Bioavailabilities of Cephalosporins

Saab, Akram N.; Dittert, Lewis W.; Hussain, Anwar

doi:10.1002/jps.2600771020

Cited by 17 publications

(7 citation statements)

References 7 publications

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“…Cephalosporin prodrug esters exhibit oral bioavailabilities of approximately 50%. Premature hydrolysis in the intestine before absorption has been discussed as a possible reason for their incomplete bioavailability (4,6,8). Hydrolysis can proceed either by enzyme-catalyzed direct hydrolysis to the parent cephalosporin (6) or via a reversible base-catalyzed isomerization yielding the ⌬2-cephalosporin ester which is rapidly cleaved to give the biologically inactive ⌬2-cephalosporin (7).…”

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confidence: 99%

“…Acquiring a better understanding of these pathways would be beneficial in designing cephalosporin pro-drug esters with improved bioavailabilities and intestinal tolerability characteristics. Therefore, we studied the degradation of three clinically relevant cephalosporin prodrug esters (cefetamet pivoxil, cefuroxime axetil, and cefpodoxime proxetil) in human intestinal juice and phosphate buffer (a well-understood model for chemical hydrolysis [5,[7][8][9]).…”

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Stability of Cephalosporin Prodrug Esters in Human Intestinal Juice: Implications for Oral Bioavailability

Stoeckel¹,

Hofheinz²,

Laneury³

et al. 1998

Antimicrob Agents Chemother

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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°C over 24 h 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 Δ2- and Δ3-cephalosporins were roughly reversed in the two incubation media. In phosphate buffer, the major degradation product was the Δ2-cephalosporin (CAT = 61%; CAE = 74%; CPD = 85%), while in intestinal juice it was the Δ3-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 1/2s] were 0.78 and 4.3 h, respectively). (iii) The two diastereoisomers of CAE and CPD were degraded at different rates in intestinal juice (for the CAE diasteroisomers, t 1/2s = 0.37 and 0.93 h; for the CPD diastereoisomers,t 1/2s = 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 Δ2 isomerization does not significantly affect the bioavailability of prodrug esters since enzymatic hydrolysis in the intestinal fluid proceeds mainly to the active Δ3-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.

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Stability of Cephalosporin Prodrug Esters in Human Intestinal Juice: Implications for Oral Bioavailability

Stoeckel¹,

Hofheinz²,

Laneury³

et al. 1998

Antimicrob Agents Chemother

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“…14 The results of these studies suggest that for cephalosporin prodrug esters, the relative rate of the delta-3 to delta-2 isomerization reaction versus the rate of cleavage of the C-4 ester group will determine whether or not active delta-3 cephalosporin free acid will reach the blood following oral administration. The isomerization takes place in buffers as well as in human plasma and appears to be independent of the nature of the alkyl functional group of the esters.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and mechanisms of decomposition of some cephalosporin prodrugs

Saab¹,

Hussain

Patel

et al. 1990

Journal of Pharmaceutical Sciences

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“…This isomerization may occur during synthetic manipulation, in vitro or in viva [ 6,7]. The A 3 to A' conversion has been known for some time [4,8] and appears to be promoted by deprotonation at the C-2 position, resulting in a double-bond rearrangement.…”

Section: Introductionmentioning

confidence: 99%

“…The A 3 to A' conversion has been known for some time [4,8] and appears to be promoted by deprotonation at the C-2 position, resulting in a double-bond rearrangement. This proton abstraction can be mediated by base [9], including the carboxylate moiety itself [ 101 or by various enzymes [ 6,7].…”

Section: Introductionmentioning

confidence: 99%

Theoretical aspects of cephalosporin isomerism

Pop

Brewster

Bodor

et al. 2009

Int. J. Quantum Chem.

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The A3 double bond of cephalosporins isomerks to the A2 position, resulting in biological inactivation of these antibiotics. This phenomenon occurs slowly in the case of cephalosporanic acids, but is rapid when the rlcarboxylate moiety is esterified or otherwise derivatized, leading to an equilibrium between the A2 and A' forms. A theoretical study of this isomerintion is demibed in the framework of two semiempirical all-valence electron molecular orbital (MO) approximations, namely MNDO and AM 1. Specifically, the methyl ester and Free ciuboxylate derivatives of both the A' and A2 isomers of 7-phenylacetamidocephalosporin were studied. The results obtained indicated that the A' derivatives were thermodynamically more stable than were the A 2 isomers both in the case of the free acids and methyl esters. These data are consistent with experimental findings and suggest that the more rapid isomerization demonstrated in the case of the esters is due primarily to kinetic rather than to thermodynamic factors.Examination of the calculated molecular structures lend support to various theories that correlate the inactivity of the A 2 isomers with spatial considerations and the degree of j3-lactam amide resonance.

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Isomerization of Cephalosporin Esters: Implications for the Prodrug Ester Approach to Enhancing the Oral Bioavailabilities of Cephalosporins

Cited by 17 publications

References 7 publications

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

Synthesis and mechanisms of decomposition of some cephalosporin prodrugs

Theoretical aspects of cephalosporin isomerism

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