Drug Biotransformation

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Katzung Pharmacology chapter 4

synthesis of which endogenous substrates share enzymes associated with metabolism of xenobiotics

steroid hormones
Vitamin D cogeners
bile acids

usual mechanism of phase I reactions

convert drug to more polar metabolite by introducing or unmasking functional group

typical functional groups used in phase I rxns

OH
NH2
SH

hallmarks of phase II rxns

combines glucuronic acid, sulfurinc acid, acetic acid, or amino acid with the polar functional group added in phase I

principal organ of drug metabolism

liver

other organs involved in drug metabolism

GI
skin
kidneys
lungs
brain

location of subcellular enzymes used in drug transformations

ER
mitochondria
cytosol
lysosomes
nuclear envelope
plasma membrane

MFO/monooxygenases

responsible for oxidative drug metabolism
require reducing agent (NADPH) and O2

typical MFO rxn in general

one O2 consumed per substrate molecule, 1 O in product and 1 in H2O

NADPH-cytochrome P450 reductase is made of

FMN and FAD

cytochrome P450

hemoprotein
terminal oxidase
inc with repeat exposure to drug

what is the rate limiting step in hepatic drug oxidations

P450 heme reduction
the reductase is less abundant than the hemoprotein

what do microsomal drug oxidations require

P450, P450 reductase, NADPH, O2

general steps of microsomal drug oxidations

1. oxidized (Fe3+) P450 + drug substrate= binary complex
2. NADPH donates electron to P450 reductase (reduces the P450-drug complex)
3. NADPH adds another e- to reductase, reducing O and making an activated O P450-substrate complex
4. transfers the activated O to the drug

what is the common feature of drugs oxidized by the p450 system

high lipid solubility

most important forms of liver P450 enzymes

CYP1A2
CYP2A6
CYP2B6
CYP2C9
CYP2D6
CYP2E1
CYP3A4

which P450 enzyme is responsible for over 50% of the Rx drugs metabolized in liver

CYP3A4

how is P450 expression induced

inc rate of synthesis or dec rate of degradation

sources of other organic compounds that induce CYP1A

tobacco smoke, charred meat, organic pyrolysis products

chemicals that induce CYP3A

dexamethasone
rifampin
mifepristone
phenobarbital
atorvastatin
hyperforin (St. John's Wort)

basic mechanism of induced P450 synthesis

AhR (cytoplasmic receptor) binds with polycyclic aromatic hydrocarbons-> into nucleus-> dimer with Arnt-> activation of reg elements of CYP1A genes

CAR

constitutive adrostane receptor
used for phenobarbital class of inducers for CYP2B6, CYP2C9, CYP3A4

PPARalpha

nuclear receptor highly expressed in liver and kidneys
lipid lowering drugs as ligands
eg- fenofibrate, gemfibrozil
mediates induction of CYP4A

RXR

retinoid X receptor
forms heterodimer with PXR, CAR, and PPARalpha upon their binding their ligand

CYP4A is responsible for

fatty acid metabolism
eg arachidonic acid

PXR

pregnane X receptor
steroid-retinoid-thyroid receptor family
mediates CYP3A induction

substrate stabilization

induction of P450s by dec degradation

how does imidizole inhibit P450

bind tightly to P450 heme iron and reduce substrate metabolism thru competitive inhibition
drug ex: cimetidine, ketoconazole

how do macrolide antibiotics inhibit P450

metabolized by CYP3A, metabolites complex the P450 heme iron and render it catalytically inactive

suicide inhibitors

inactivators that attack the heme or protein moiety

drug conjugates

drugs coupled with endogenous substance (phase II rxn)
polar molecules that are readily excreted and often inactive

where are transferases located

microsome or cytosol

which transferases are the most dominant

UGTs
Uridine 5'diphosphate glucuronosyl transferases

mechanisms of SULTs

sulfotransferases
sulfation of substrates using PAPS (3'phosphoadenosine 5'phosphosulfate- sulfur donor)

GSH

glutathione

GST

glutathione transferases
metab drugs, xenobiotics, leukotrienes, prostaglandins

NATs

cytosolic N-acetyltransferases
use acetyl CoA as cofactor for metabolizing chemicals with aromatic amine or hydrazine

SAMe

S-adenosyl-L-methionine
mediates O, N, and S methylation of drugs/xenobiotics using methyltransferases

EHs

epoxide hydrolases
hydrolyze endobiotic, drug, and xenobiotic epoxides from P450 oxidations

what plays a critical role in the regulation of drug conjugations

nutrition because endogenous substrates originate in teh diet

normal mechanism of acetaminophen metabolism

glucuronidation and sulfation (95%) and P450 dependent GSH conjugation (5%)

when does acetaminophen become toxic

when levels saturate the P450 pathway, no hepatic GSH available for conjugation, toxic metabolite accumulates, damages liver

why is GSH not effective antidote for acetaminophen induced hepatotoxicity

doesn't readily cross cell membranes

2 effective antidotes to acetaminophen overdosage

cysteamine
N-acetylcysteine (safer)

what factors influence individual variations in drug distribution, metabolism, and elimination

genetic factors, age, sex, liver size, liver function, circadian rhythm, temperature, nutrition, environment (exposure to inducers/inhibitors of drug metabolism)

individual differences in metabolic rate depend on

the nature of the drug

slow acetylator phenotype

50% blacks/whites in US, more freq in Europeans at high altitudes
higher incidence of drug-induced autoimmune disorders and bicyclic aromatic amine-induced bladder cancer

genetic polymorphisms in UGT are associated with

hyperbirubinemic diseases and impaired drug conjugation/elimination

genetic polymorphisms in GST associated with

significant adverse effects and toxicities of drugs dependent on GSH conjugation pathway

debrisoquin-sparteine oxidation polymorphism

3-10% whites, auto recessive
CYP2D6 oxidations of debrisoquin, etc are impaired
faulty expression of the P450 protein

ultrarapid metabolism

CYP2D6 polymorphism with up to 13 repeat genes in tandem
common in Ethiopians and Saudi Arabians

CYP2C19 polymorphism

stereoselective aromatic 4-hydroxylation of mephenytoin
auto recessive
3-5% caucasians, 18-23% Japanese
poor metabolizers completely lack enzyme activity

CYP2C9 polymorphism

CYP2C9*2- impaired functional rxns with P450 reductase
CYP2C9*3- lowered affinity for many substrates

CYP2C9*3 polymorphism would affect metabolism of which drugs

warfarin, henytoin, losartan, tolbutamide, some NSAIDs

significance of low CYP2A6 activity

smokers with this gene consume less and have lower incidence of lung cancer

Ziegler's enzyme

falvin monooxygenase
polymorphisms with low activity result in fish-odor syndrome

charbroiled foods and cruciferous vegetables induce which enzyme

CYP1A

grapefruit juice inhibits which enzyme

CYP3A

examples of enzyme-inducing drugs

sedative-hypnotics
antipsychotics
anticonvulsants
rifampin (anti-TB)
insecticides

75% of biotransformation from these 2 enzymes

CYP3A4
CYP2D6

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