Reduction drug metabolism

Metabolic reactions in the liver and the small intestine are well documented [24]. However, only sparse information is available on drug metabolism in the eolon. Drug metabolism in the colon can be brought about by the host enzymes in the epithelial cells or by the microbial enzymes in the gut flora. Metabolie aetivities in the wall of the colon can be attributed to the eytochrome P450, esterases, amidases, and various transferases [25]. Reductive drug metabolism does not appear to be important at this site. 

R. Jonen-Kern, H. G. Jonen, R. R. Schupp, K. Minck, G. F. Kahl, and K. J. Netter, Reductive drug metabolism in isolated perfused rat liver under restricted oxygen supply, Xenobio-ticaS, 271-280 (1978). 

The next process we consider is drug metabolism. The study of oxidation reactions in compounds such as benzo (a) pyrene has emphasized the P450-dependent oxidation systems of the liver toxicologists have virtually Ignored other potentially important oxidizing systems. Future research may find drug-oxidation systems which are not P450-linked, and even other membrane-bound and non-membrane-bound oxidative and reductive systems in whole animal cells. 

It must be recognized that developmental differences in hepatic drug metabolism occur consequent to reductions in the activity of specific drug-metabolizing enzymes and their respective isoforms. For most enzymes, the greatest reduction of activity is seen in premature infants where immature function may also reflect continued organogenesis. This... 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

The reduction in therapeutic effectiveness that can occur when antihistamines are given for long periods is probably related to an induction of hepatic drug-metabolizing enzymes. Children tend to eliminate antihistamines more rapidly than adults, while individuals with hepatic impairment may eliminate them more slowly. 

Phase I metabolic reactions involve oxidation, reduction, or hydrolysis of the parent molecule, resulting in the formation of a more polar compound. Phase 1 reactions are mediated by the cytochrome P450 (GYP) family of enzymes. While metabolism used to be thought of as the body s detoxification process, phase I metabolites may be equally or even more pharmacologically active than the parent compound. Drug metabolism in general, and CYP-based mechanisms in particular, are discussed in detail in Chapter 5. 

Figure 3.7 Examples of drug metabolism by oxidative and reductive pathways.

The liver is the principal site of drug metabolism. Hepatic drug metabolism is usually classified into two distinct phases. Phase I reactions are oxidation, reduction or hydrolysis. One of the most important systems that catalyse oxidation are the haem-containing cytochrome P-450 enzymes. 

Some drugs are metabolized so readily that even marked reduction in liver function does not significantly prolong their action. However, cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited (Table 4-7). These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. Pulmonary disease may also affect drug metabolism, as indicated by the impaired... 

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