Kinetics Lecture 10-28 Part 22

Front 1

Liver

responsible for a major part of drug metabolism

Back 1

true

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Liver

metabolism makes drug molecules more:

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hydrophilic--> less prone to protein binding --> more susceptible to excretion

Front 3

Liver

secretes:

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bile acids

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Liver

the basic unit:

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liver lobule (parenchymal cells + bile cannaliculi + sinusoids)

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Liver

parenchymal cells=

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hepatocytes

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Liver blood supply

receives blood from:

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- hepatic artery (25%) carries oxygen
- hepatic portal vein (75%) carries nutrients and drugs from GI tract

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liver blood supply

hepatic artery and portal vein fuse within:

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the liver and mix in the sinusoids

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liver blood supply

blood leaves the liver via:

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the hepatic vein

Front 9

biotransformation enzymes

the most studied enzymes are called:

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mixed-function oxidases (MFO)

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biotransformation enzymes

localized in:

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hepatocytes

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biotransformation enzymes

associated with:

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endoplasmic reticulum

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biotransformation enzymes

can be isolated as:

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microsomal fraction- membrane vesicles called microsomes- after hepatocyte disruption and differential centrifugation

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biotransformation enzymes

main component:

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CYP450

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Mixed-function oxidases (MFO)

fully functional system contains:

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--two enzymes (CYP450-diff isozymes)
(NADPH-cyp450
reductase)
--cofactor: NADP+ (NADPH)
--substrates (molecular oxygen, drug)
--phosphlipids

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CYP450

inducible (barbiturates, smoke)

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true

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CYP450

multiple isoenzymes differing in:

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drug specificity

Front 17

CYP450

heme protein containing iron, some isoenzymes with a large cavity that causes interesting phenomena:

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- lower specificity than most other enzymes
- cooperativity in enzyme kinetics, sometimes two substrate molecules fit inside the cavity
- drug drug interactions

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CYP450

binds predominantly :

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lipid-soluble (lipophilic) drugs

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Phase I reactions

usually occur:

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first and cause a "smaller" change than phase II

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Phase I rxn

introduce or expose a :

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functional group

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phase I reactions

examples:

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hydroxylation
dealkylation
deamination
hydrolysis
reduction

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phase II reactions

connect the drugs or their metabolites from phase I reactions with:

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physiological compounds (glucuronate, glycine, sulphate, glutathione)

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phase II reactions

one reaction partner must:

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be in high energy form (bound to a nucleotide)

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phase II reactions

reactions are catalyzed by proper transferases, which have:

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low Michaelis constant values and can be saturated at comparatively low concentrations

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hepatic elimination scheme

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see pg 2 slide 5

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metabolism in one hepatocyte

spontaneous reactions and M-M metabolism determine the:

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temporal change in the metabolite concentration in each hepatocyte
([D] = [D]p for drugs transported quickly)

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metabolism in liver: intrinsic clearance

the drug amount metabolized in the liver is:

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the sum of drug amounts metabolized by individual hepatocytes

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hepatic clearance refers to cp

intrinsic clearance is:

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the sum of clearances of individual hepatocytes

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hepatic clearance refers to cp

hepatic clearance is:

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the metabolic rate ([D]=[D]p) divided by cp

Clh= fu * Clint

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extraction ratio and blood flow

extraction ratio is:

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the fraction of the drug eliminated by the organ in one pass

ER= (ca - cv)/ ca

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physiologic hepatic clearance

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

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physiologic hepatic clearance

perfusion limitation for fast metabolism:

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(Clh >>Q)

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physiologic hepatic clearance and hepatic clearance

physiologic hepatic clearance cannot:

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be higher than blood flow Q, even if the liver itself is able to eliminate faster

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biliary excretion

what type of secretion?

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active secretion (saturable, energy driven) affects mainly water-soluble drugs

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biliary excretion

bile flow:

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0.5 - 0.8 mL/min
pH~7.4

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enterohepatic circulation

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see pg 4 slide 1

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excretion vs metabolism

the amounts of unchanged drug and of metabolites are:

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in the same relation as the clearance of excretion and metabolism