Phase I: Often the first step in biotransformation with formation of product susceptible to phase II conjugative reaction.
Includes: oxidation, reduction, deamination, dealkylation, and hydrolysis.
Following phase I reactions, the metabolites are typically more polar which increases the likelihood of their excretion by the kidney.
Phase I metabolic products may be further metabolized or may be directly excreted into urine.
phase I reactions are functionalization reactions, introduction of a new functional group), frequently adding a -OH, --SH, or -NH2 , or exposing an existing functional group (e.g. hydrolysis of ester linkage)
Phase I reactions may increase, decrease, or leave unaltered the drug's pharmacologic activity.
they are usually catalyzed by oxidases located in smooth endoplasmic reticulum, mainly cytochome P450 enzymes
Phase I reactions require: cytochrome P450 hemoprotein, NADPH-cytochrome P450 reductase, NADPH, and molecular oxygen
o Drug + O2 + NADPH + H+ = Drug transformed + H20 + NADP+
CYP450s are mainly in hepatocytes, but also cells of the kidney, lung, intestine,
skin, testis, brain
each CYP450 oxidizes many substrates (with some selectivity for classes of chemicals)
10: 1 in the liver
is expressed universally in liver tissue
is further induced by smoking (tobacco), ingestion of grilled meats
CYP2C9/10 and CYP2C18/19
collectively, the 2C family is very important in drug metabolism, e.g. taxol, phenytoin, diclofenac, piroxicam, diazepam, cycloguanil, imipramine - Tax Imperial Diamonds Cyclically, PPD
expressed mainly in liver
important in the metabolism of: codeine, debrisoquine, propranolol, captopril, dextromethorphan, nortryptiline - No, Captain Dexter Protects D Codes
a genetic polymorphism (identified with sparteine) affects 10% of Caucasions, 2% of Mongoloids
expressed mainly in liver, and also peripheral lymphocytes
induced by ethanol (major role in Ethanol metabolism in alcoholics)
important in metabolism of a range of Endustrial chemicals, e.g. benzene, styrene, vinyl chloride, carbon tetrachloride, chloroform, ethyl carbamate
most abundant human isoform (liver, intestine)
induced by barbiturates, rifampicin, glucocorticoids
most important CYP450 in drug metabolism, e.g. nifedipine, quinidine, taxol, erythromycin, contraceptives, warfarin, cyclosporin, midazolam, lidocaine
War Taxes Every Country Cyclically, Middle Lives Fed up Quickly