Cephaloridine - Adverse Effects - Metabolism

Metabolism

Cephaloridine is excreted in the urine without undergoing metabolism. It inhibits organic ion transport in the kidney. This process is preceded by the lipid peroxidation. Thereafter, probably a combination of events, such as formation of a reactive intermediate, a free radical and stimulation of lipid peroxidation, lead to peroxidative damage to cell membranes and mitochondria. It is not yet clear whether metabolic activation by cytochromes P-450, chemical rearrangements, reductive activation or all these actions are involved.

The hypotheses made about the mechanism of action causing the toxiciy of cephaloridine are:

• Reactive metabolites are formed by cytochromes P-450 or emerge from destabilization of the β –lactam ring. Metabolic activation of the drugs might take place via cytochromes P-450, producing reactive metabolites. This hypothesis is based on the behaviour of some inhibitors of CYTP450, which decrease the toxicity, and some inducers of the monooxygenases which increase toxicity. It could also be possible that a reactive intermediate is formed due to the unstable β -lactam ring. The pyridinium side-group of cephaloridine has unstable bonds to the core of the compound (in comparison with other cephalosporins). When this side-group leaves, the β –lactam ring is destabalized by intramolecular electron shifts. Thus, the leaving group creates a reactive product.
• Both lipid peroxidation and oxidative stress can cause membrane damage. Lipid peroxidation and oxidative stress take place as lipid peroxidation products, such as malondialdehyde, have been detected. Reduced glutathione (GSH) and NADPH are both depleted. Consequently, GSSG cannot be reduced to GSH. This leads to an increased toxicity since oxidative stress cannot be reduced. In addition, nephrotoxicity is augmented by deficiency of selenium or tocopherol. The pyridinium side-group interacts with the reduced NADP in a redox cycle. It has been suggested that superoxide anion radicals and hydroxyl radicals may be formed and that lipid peroxidation could be responsible for the toxicity of cephaloridine.
• Damage to the mitochondria and intracellular respiratory processes and reduced mitochondrial respiration can cause nephrotoxicity. The previously mentioned damages have been detected after exposure to cephalosporins. β-lactam antibiotics injure mitochondria by an attack on the metabolic substrate carriers of the inner membrane. Respiratory toxicity is caused by inactivation of mitochondrial anion substrate carriers.