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37 Cards in this Set

  • Front
  • Back

responsible for a major part of drug metabolism

metabolism makes drug molecules more:
hydrophilic--> less prone to protein binding --> more susceptible to excretion

bile acids

the basic unit:
liver lobule (parenchymal cells + bile cannaliculi + sinusoids)

parenchymal cells=
Liver blood supply

receives blood from:
- hepatic artery (25%) carries oxygen
- hepatic portal vein (75%) carries nutrients and drugs from GI tract
liver blood supply

hepatic artery and portal vein fuse within:
the liver and mix in the sinusoids
liver blood supply

blood leaves the liver via:
the hepatic vein
biotransformation enzymes

the most studied enzymes are called:
mixed-function oxidases (MFO)
biotransformation enzymes

localized in:
biotransformation enzymes

associated with:
endoplasmic reticulum
biotransformation enzymes

can be isolated as:
microsomal fraction- membrane vesicles called microsomes- after hepatocyte disruption and differential centrifugation
biotransformation enzymes

main component:
Mixed-function oxidases (MFO)

fully functional system contains:
--two enzymes (CYP450-diff isozymes)
--cofactor: NADP+ (NADPH)
--substrates (molecular oxygen, drug)

inducible (barbiturates, smoke)

multiple isoenzymes differing in:
drug specificity

heme protein containing iron, some isoenzymes with a large cavity that causes interesting phenomena:
- lower specificity than most other enzymes
- cooperativity in enzyme kinetics, sometimes two substrate molecules fit inside the cavity
- drug drug interactions

binds predominantly :
lipid-soluble (lipophilic) drugs
Phase I reactions

usually occur:
first and cause a "smaller" change than phase II
Phase I rxn

introduce or expose a :
functional group
phase I reactions

phase II reactions

connect the drugs or their metabolites from phase I reactions with:
physiological compounds (glucuronate, glycine, sulphate, glutathione)
phase II reactions

one reaction partner must:
be in high energy form (bound to a nucleotide)
phase II reactions

reactions are catalyzed by proper transferases, which have:
low Michaelis constant values and can be saturated at comparatively low concentrations
hepatic elimination scheme
see pg 2 slide 5
metabolism in one hepatocyte

spontaneous reactions and M-M metabolism determine the:
temporal change in the metabolite concentration in each hepatocyte
([D] = [D]p for drugs transported quickly)
metabolism in liver: intrinsic clearance

the drug amount metabolized in the liver is:
the sum of drug amounts metabolized by individual hepatocytes
hepatic clearance refers to cp

intrinsic clearance is:
the sum of clearances of individual hepatocytes
hepatic clearance refers to cp

hepatic clearance is:
the metabolic rate ([D]=[D]p) divided by cp

Clh= fu * Clint
extraction ratio and blood flow

extraction ratio is:
the fraction of the drug eliminated by the organ in one pass

ER= (ca - cv)/ ca
physiologic hepatic clearance
- the actual clearance observed in the patient
- takes into acct the blood flow (Q) limitation
Clhp= Q*Clh/Q + Clh
physiologic hepatic clearance

perfusion limitation for fast metabolism:
(Clh >>Q)
physiologic hepatic clearance and hepatic clearance

physiologic hepatic clearance cannot:
be higher than blood flow Q, even if the liver itself is able to eliminate faster
biliary excretion

what type of secretion?
active secretion (saturable, energy driven) affects mainly water-soluble drugs
biliary excretion

bile flow:
0.5 - 0.8 mL/min
enterohepatic circulation
see pg 4 slide 1
excretion vs metabolism

the amounts of unchanged drug and of metabolites are:
in the same relation as the clearance of excretion and metabolism