Cephalexin oral absorption

Fewer cephalosporins have been of clinical interest for oral administration. Studies of cefatrizine (BLS-640 SKF 60771) (7) have continued to determine in vitro characteristics,65-67 human pharmacokinetics,66 68,69 and clinical effectiveness.69-71 Extensive clinical trial data documented the effectiveness of cefadroxil (BLS-578 -OH cephalexin).72 Cefaclor (Lilly 99638) ( ) has been shown in in vitro studies to have better activity than cephalexin against gram-negative bacteria, especially H. influenzae. 56 60 73 7 The excellent oral absorption in mice, rats, and dogs paralleled that of cephalexin.75 Metabolism was observed in dogs76 but not in rodents. Human pharmacology studies indicated that cefaclor gave acceptable blood and urine levels.77... 

Semisynthetic Cephalosporins. Once the structure of cephalosporin C became known (98), attempts were made to find chemically modified analogs having superior biological properties. This was successfully achieved with the synthesis of cephalothin, cephaloridine, cephalogly-cine, and cephalexin (Figure 20). In the first two, in vitro potency was enhanced as much as 10,000 fold (99), in the latter two oral absorption... 

Cephalexin occurs as a white crystalline monohydratc. It is freely. soluble in water, rcsi.stant to acid, and ab.sorbed well orally. Food does not interfere with its absorption. Because of minimal protein binding and nearly exclusive renal excretion, cephalexin is recommended particularly for the treatment of urinary tract infections. It is also sometimes used for upper respiratory tract infections. Its spectrum of activity is very similar to those of cephalodiin and ccphalori-dine. Cephalexin is. somewhat less potent than these two agents after parenteral administration and. therefore, is inferior to them for the treatment of serious systemic infections. 

A second example is cephalexin (Fig. 10.47) which has no substitution at position 3. This is one of the few cephalosporins which is absorbed through the gut wall and can be taken orally. This better absorption appears to be related to the presence of the 3-methyl group. Usually, the presence of such a group lowers the activity of cephalosporins, but if the correct 7-acylamino group is present as in cephalexin, then activity can be retained. The mechanism of the absorption through the gut wall is poorly understood and therefore it is not clear why the 3-methyl group is so advantageous. 

Cephradine is similar in structure to cephalexin and almost identical in its clinical use. Cephradine is not metabolized and, after rapid absorption from the GI tract, is excreted unchanged in the urine. Because cephradine is so well absorbed, concentrations in plasma are nearly equivalent after oral or intramuscular administration. 

All orally active (3-lactams carry an unsubstituted or modified D-phenylglycine side group in the A-terminus position and therefore should have affinities similar to di- and tripeptides with an A-terminal D-amino acid [14]. The stereoselective transport of (3-lactam antibiotics is of particular interest because the L-isomer of aminocephalosporin failed to be absorbed in vivo to a significant extent [15]. However, a study on d- and L-enantiomers of cephalexin and loracarbef demonstrated the higher affinity of the L-isomer to oligopeptide transporter than the o-isomer (Fig. 5) [16]. Consequently, the apparent low absorption rate of L-isomers of amino cephalosporines does not appear to be due to lack of transport by the peptide transporter, but, more likely, because of the rapid enzymatic... 

These results closely parallel those obtained with cephalexin in similar studies. In dogs, cefaclor is more labile to metabolism. Only a minor fraction of the administered dose is eliminated unchanged by the kidney. Total radiocarbon levels in both blood and urine were at considerably higher levels than could be present in unchanged antibiotic. As in the other species, biliary excretion in the dog plays only a minor role in the elimination of parent antibiotic and its metabolites (Sullivan et al., 1976). Other studies in the dog also showed rapid absorption of cefaclor following oral and intramuscular administration. Most of the dose was renally excreted, about 50% as intact antibiotic and the other 50% as microbiologically inactive degradation products. In the dog, cefaclor was shown to concentrate in the kidney and liver and to penetrate at lower levels into hard bone and synovial fluid (Quay et al., 1976). 

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