Enzyme drug-metabolising

Walker, C.H. (1980). Species variations in some hepatic microsomal enzymes that metabolise xenobiotics. Progress in Drug Metabolism 5, 118-164. 

KALL M A, VANG o and CLAUSEN J (1996) Effects of dietary broccoli on human in vivo drug metabolising enzymes Evaluation of caffeine, oestrone and chloroxazone metabolism. Carcinogenesis 17 793-9. 

Masimirembwa, C. M. Hasler, J. A. (1997). Genetic polymorphism of drug metabolising enzymes in African populations implications for the use of neuroleptics and antidepressants. Brain. Res. Bull., 44(5), 561-71. 

Other carotenoids, such as canthaxanthin and astaxanthin have been recognized as potent inducers of CYP1A1 and 1A2 in rat liver (Gradelet et al., 1998). The administration of lycopene to rats was shown to induce liver CYP types 1 Al/2, 2B1/2, and 3A in a dose-dependent manner (Breinholt et al., 2000). The observation that these enzymatic activities were induced at very low lycopene plasma levels suggests that modulation of drug metabolising enzymes by carotenoids may be relevant to humans (Breinholt et al., 2000). 

K. P., Comparative studies of drug-metabolising enzymes in dog, monkey, and human small intestine, and in Caco-2 cells, Drug Metab. 

N., Muraro, G. B., Tissue distribution of drug metabolising enzymes in humans, Xenobiotica 1988, 18, 849-856. 

L. M., Hochman, J. H., Tran, L. O., Vyas, K. P., Comparative studies of drug metabolising enzymes in dog, monkey and human small intestines and in Caco-2 cells, Drug Metab. Disp. 1996, 24, 634-642. 

Bosch, T.M., Meijerman, I., Beijnen, J.H., et al. (2006) Genetic polymorphisms of drug-metabolising enzymes and drag transporters in the chemotherapeutic treatment of cancer. Clin. Pharmacokinet. 45, 253-285. 

Choudhury RB, Haque SJ, Poddar MK. (1987) In vitro and in vivo effects of kalmegh (Andrographis paniculata) extract and andrographolide on hepatic microsomal drug metabolising enzymes. Planta Med 53 135-140. 

Investigation of potential adverse interactions with drugs likely to be co-prescribed with the test drug may also be required. A generalised approach, such as the determination of effects on hepatic drug metabolising enzymes, may be sufficient, but in most cases, a number of drug-specific interaction studies will also be required. 

Pharmacokinetics and metabolism - absorption, distribution, metabolism and excretion (ADME), including potential for interactions, polymorphisms of drug metabolising enzymes and exposures in man predicted from interspecies allometric scaling... 

If volunteers are required to give specimens for genotyping for drug metabolising enzymes or for proteins that might be involved in... 

Tolerability" should not be confused with the term "tolerance", which describes the diminution in effects of a drug on prolonged exposure. Tolerance may be due to increased clearance because of autoinduction of the enzymes that metabolise the drug, such as occurs with some antiepileptic drugs, for example, carbamazepine. Tolerance may also result from altered pharmacodynamics, which is common with drugs acting on the CNS. 

Levy RH et al. Metabolic Drug Interactions. With information on drug metabolising enzymes, inhibitors and inducers. 

The importance of these enzymes for drug interactions is that enzyme inducers and inhibitors may preferentially affect certain isoforms and consequently may only affect the metabolism of selected drugs. For example, ketoconazole has the potential to inhibit the metabolism of drugs metabolised to a great extent by the sub-family 3A (e.g. midazolam) but not of those metabolised by sub-family 1A (e.g. theophylline), 2C (e.g. diazepam), or 2D (e.g. metaprolol). In contrast, although fluconazole is a weaker inhibitor of the sub-family 3A than ketoconazole, it also inhibits the sub-family 2C, and so the interactions of fluconazole differ from those of ketoconazole. 

NTIOO Nair, U. ]., N. Ammigan, J. R. Kul-karni, and S. V. Bhide. Species difference in intestinal drug metabolising enzymes in mouse, rat and hamster and their inducibility by masheri, a pyro-lysed tobacco product. Indian J Exp Biol 1991 29(3) 256-258. 

Liver They induce microsomal drug metabolising enzyme thus they increase the rate of metabolism of number of drugs. 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

Omeprazole can inhibit the metabolism of drugs metabolised mainly by the cytochrome P-450 enzyme subfamily 2C (diazepam, phenytoin), but not of those metabolished by subfamilies lA (caffeine, theophylline), 2D (metoprolol, propranolol), and 3A (ciclosporin, lidocaine (lignocaine), quinidine). Since relatively few drugs are metabolised mainly by 2C compared with 2D and 3A, the potential for omeprazole to interfere with the metabolism of other drugs appears to be limited, but the half lives of diazepam and phenytoin are prolonged as much as by cimetidine. 

Nebert DW. The genetic regulation of drug-metabolising enzymes. Drug Metab Disp 1986 16 1. 

Johnson TN. The development of drug metabolising enzymes and their influence on the susceptibility to adverse drug reactions in children. Toxicology. 2003 192 37-48. 

Oscarson M. Pharmacogenetics of drug metabolising enzymes importance for personalized medicine. Clin Chem Lab Med. 2003 41 573-580. 

Fuhr U. Induction of drug metabolising enzymes pharmacokinetic and toxicological consequences in humans. Clin Pharmacokinet 2000 38 493-504. 

Ingelman-Sundberg M. Human drug metabolising cytochrome P450 enzymes properties and polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 2004 369 89-104. 

Wang H, LeCluyse EL. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 2003 42 1331-1357. 

In summary, CACO-2 cells express many enzymes characteristic for intestinal cells involved in drag metabolism. The major drug metabolising enzyme, CYP 3A, is active only in selected clones pointing to polyclonal origin of CACO-2 and the necessity to characterize CACO-2 cells extensively for growth and experimental conditions used for given experiments. 

For safety reasons, it is important to identify, and perhaps eliminate, drugs from further development if they are subject to polymorphic metabolism or extensive metabolism by key human enzymes. Knowledge about the cytochrome P450 (CYP450) superfamily of drug metabolising enzymes is of particular interest. 

Genetics Genetic differences in drug metabolising enzymes may predispose certain patients to hepatotoxicity. For example, the hlack and Hispanic population may he more prone to isoniazid toxicity Genetics may play a role in diclofenac hepatotoxicity... 

The individual drug-metabolising enzymes follow different developmental patterns. An indication of when the various enzymes are first expressed is given below ... 

Hyperlipidaemia rarely occurs in cirrhotic patients. Patients with decompensated disease should not be given medical treatment for hyperlipidaemia medications should be withheld during the period of decompensation and then reinitiated according to the principles outlined in Case 3 above, when the patient s synthetic fimction recovers. Note that chronic alcohol use can induce CYP450 enzymes drugs which are metabolised by this system may be cleared more quickly. 

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