Penamaldates

A new metabolite detected in human urine by HPLC was identified as amoxicillin penamaldic acid, XI, on the basis of spectroscopic investigations of material, obtained by in vitro treatment of amoxicillin penicilloic acid, which was shown to co-ehite with the metabolite on HPLC [ISO], More detailed UV and NMR studies on material prepared in the same way showed that the assignment of XI was incorrect and that the new metabolite was the 5S diastereoisomer of the penicilloic acid, V, produced by epimerisation of the 5R isomer formed by hydrolysis of amoxicillin [43]. The presence of both isomers in rat and human urine has recently been confirmed by high field proton NMR [151]. 

Electronic absorption spectroscopy did not provide any direct evidence for the characterization of penicillins, since they show little absorption in the. near ultra-violet or visible regions which can be associated with chromo-phoric groups. However, ultra-violet absorption spectra were useful in solving the structures of some of the degradation products7. On reaction with alcohols, penicillins give a-esters of penidlloates, IV, which are quantitatively converted to penamaldates, V, in the presence of alcoholic mercuric OO... 

Fig. 23. Reaction of penicilloic acid (/) with cystine to yield penamaldic acid-cysteine mixed disulfide (//). Subsequent hydrolysis of II yields penicillamine-cysteine mixed disulfide (III) and penaldic acid (IV)...

However, in these studies, no serious attempts were made ot assess the antibodies specific for penamaldate and penicillamine determinants, which are precisely those which could be expected. Benzylpenicilloic acid, when applied to guinea pig skin, seems able through whatever immunochemical mechanism to induce contact hypersensitivity (Levine 1960 a). 

D-Penicillamine may arise directly from penicilloic acid or through formation of a penicillamine-cysteine mixed disulfide, following a penamaldate rearrangement (Levine 1960 c Yemal et al. 1978). This reaction also occurs with functional derivatives of the alpha-carboxylic group of penicilloic acid (Schneider et al. 1973). The penicillamine determinant may therefore arise in vivo from any penicilloyl conjugate. 

In the cephalosporins, the formation of penicillenic acid equivalents appears difficult and the corresponding intermediates would generate penamaldates (Fig. 10). Furthermore, the presence of a dihydrothiazine ring instead of a thiazolidine ring makes the formation of a penicilloic acid equivalent unlikely and that of a penicillamine analogue impossible (Dewdney 1977). 

The Penicillenate, Penicilloic Acid, Penicillamine, and Penamaldate Determinants... 

Fig. 5.6 Pathways for the formation of penicilloyl, penicillenate, penicilloic acid, penamaldate, penicillamine, and...

The work outlined above, and the interpretation of the chemical findings, indicates that as far as any resultant determinants are concerned, aminolysis results in structures in which only the R1 side chain, the attached amide, and remnants of the p-lactam ring remain from the original cephalosporin molecule. The resultant penaldate- and any penamaldate-like structures finked to carrier protein therefore represent hapten-carrier complexes that may interact with side chain (Rl)-specific IgE antibodies in allergic responses to therapeutic dosage of cephalosporin drugs. 

Investigations of the formation of antigenic and allergenic determinants of benzylpenicil-hn have identified a list of determinants that inclndes the penicUloyl, penidllenate, peni-cUloic acid, peniUoic acid, penamaldate, penicoyl, penicillanyl, and penicillamine stmctnres. 

Aminolysis of cephalosporins in the presence of polylysine or protein produces unstable intermediates that decompose to penaldate and ultimately penamaldate structures. This results in structures in which only the R1 side... 

The pH-independent epimerisation of penicilloic acid at C(5) probably occurs by unimolecular ring opening of the thiazolidine to form the iminium ion tautomer of penamaldic acid [74]. There are two possible explanations for the base-catalysed reaction. Above pH 12 deprotonation of the iminium ion could become faster than ring closure, and the rate of epimerisation would increase because the steady state concentration of the ring-opened thiazolidine is increased. Alternatively, epimerisation could occur by the penamaldate mechanism followed by penicilloyl esters (Davis and Page, 1985). 

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