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Pharmacokinetics > Hepatic Clearance, Drug Metabolism, and Pharmacogenomics - Pre Lecture > Flashcards

Hepatic Clearance, Drug Metabolism, and Pharmacogenomics - Pre Lecture Flashcards

1
Q

Can lipophilic drugs be eliminated by renal excretion? Why or why not?

A

No, they undergo tubular reabsorption in the distal tubule

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2
Q

Describe the excretion pathway of a lipophilic drug?

A
  1. Glomerular filtration
  2. Excretion is augmented by drug transporters in proximal tubule
  3. When they reach the distal tubule, the concentration gradient between the tubule and the blood, combined with their good membrane permeability properties, will result in extensive, if not complete, reabsorption of these molecules
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3
Q

What is the primary purpose of hepatic metabolism?

A

To create more hydrophilic molecules that will not undergo tubular reabsorption and trus can be eliminated from the body in the urine

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4
Q

How are most lipophilic drugs eliminated?

A

Metabolism or biotransformation

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5
Q

How much of US prescribed drugs are eliminated by metabolism?

A

70%

Metabolites have greater water solubility than that of the parent drug, but occasionally, metabolites are less soluble.

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6
Q

What is hepatic clearance?

A

The volume of blood that perfuses the liver and get cleared of the drug per unit of time

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7
Q

What is extraction ratio?

A

The fraction of drug presented to the liver that is eliminated during a single pass

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8
Q

What is intrinsic clearance?

A

Pure measure of the ability of the liver enzymes to metabolize a drug

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9
Q

What factors effect hepatic clearance?

A

Protein binding and hepatic blood flow

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10
Q

What factors effect intrinsic clearance?

A

The affinity of a drug for the enzymes and the amount of enzymes present

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11
Q

Where does most of drug metabolism take place?

A

Liver containing an abundance of metabolism enzymes

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12
Q

How does enzyme location play apart in metabolism?

A

Affects a drug’s PK characteristics

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13
Q

Describe the importance of enzymes in the intestinal enterocyte?

A

Causes significant pre-systemic extraction and drastically reduce the oral bioavailability of some drugs

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14
Q

What are the categories hepatic metabolism?

A

Phase 1 and 2

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15
Q

What is phase 1?

A

Result in small chemical modifications of the drug molecule

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16
Q

What reactions are phase 1?

A
  1. Oxidation
  2. Addition of hydroxyl group
  3. Removal of methyl group
  4. Reduction
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17
Q

List enzymes of phase 1?

A
  1. flavin monooxygenase
  2. alcohol dehydrogenase
  3. aldehyde dehydrogenase
  4. xanthine oxidase
  5. cytochrome P450 (CYP) enzyme system
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18
Q

What enzymes is the most important for phase 1?

A

cytochrome P450 (CYP) enzyme system that is responsible for 70% of drug eliminated by metabolism

19
Q

What is phase 2?

A

The parent drug or product of phase 1 metabolism is conjugated with polar function

20
Q

What molecules are conjugated in phase 2?

A

Glucurinide, sulfate glutathione

21
Q

What is the most important enzyme of phase 2?

A

UDP- glucuronosyltransferases (UGTs) estimated to be responsible for 10% of drugs eliminated by metabolism

22
Q

What is an alternative route phase 1 and more often phase 2 metabolites are excreted?

A

Bile

23
Q

Who much of therapeutic drugs are metabolized by CYP3A4?

A

50%

24
Q

How much of oxidative phase 1 are metabolzizedby CYP?

A

80%

25
Q

What are the 4 CYP enzymes?

A

CYP3A4, CYP1D9, CYP2C19, CYP2C9

26
Q

What is CYP2D6?

A

Constitutes less that 5% of total hepatic CYP, yet is responsible for the metabolism of around 20% of drugs metabolized by the system

27
Q

What is most abundant CYP and metabolizes the greatest number of drug?

A

CYP3A4

28
Q

What is the problem with CYP2C9?

A

Thye metabolize a large number of drugs

29
Q

What is glucuronidation?

A

Around 10% of drugs are metabolized by the UGTs to glucuronide metabolites

30
Q

What are the isoforms of UGT?

A

UGT1A1, 1A4, 1A6, 1A9, 2B7, 2B15, UGT2B7

31
Q

What UGT isoform has the largest number of drug isoforms?

A

UGT2B7

32
Q

What are the effect of having many UGT isoforms?

A

Could predispose certain individuals to either toxic or sub-therapeutic concentrations of the substrates of UGTs

33
Q

What may contribute to UGT variability?

A

Genetic factors and induction by alcohol and smoking

34
Q

What is found in every biological process of drug response?

A

Proteins

35
Q

What are genes?

A

DNA portions that contain information to determine amino acid sequence of proteins

36
Q

What will occur DNA has sequence variations?

A

The proteins may not be produced or functioning properly

37
Q

What determine a patient’s response to drug therapy?

A

PK and pharmacodynamics properties of the drugs

Genetic variations will affect ADME processes and receptors

38
Q

What are the most pharmacologically relevant genetic variants?

A
  1. Genes that encode drug-metabolizing enzymes
  2. Drug transporter proteins
  3. Drug targets such as receptors and ion-channels
39
Q

What plays an important role in the PK of drugs?

A

Drug-metabolizing enzymes and drug transporters

40
Q

How will mutations affect drug metabolizing enzymes?

A
  1. Enzyme morphology altering the capacity of the metabolizing enzymes
  2. Drug transporters
  3. ADME and receptors
  4. Receptor morphology altering drug binding affinity
41
Q

What is pharmacogenetics?

A

Studies the effect of single gene or a few genes on drug response

42
Q

What is pharmacogenomics?

A

Studies the action of multiple genes on drug responses

43
Q

What is the difference between pharmacogenetics and genomics?

A

Genomtics: Whole-genome application, broader, implies a recognition that more that one genetic variant may contribute to variation in drug response
Genetics: Evolved to genomics

Pharmacokinetics (29 decks)

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