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PK and PA Lectures > Hepatic clearance > Flashcards

Hepatic clearance Flashcards

1
Q

How does drug elimination occur?

A

Irreversible loss of drug from the body

> Metabolism: conversion of one chemical entity to another

> Excretion: loss of chemically unchanged drug

Unchanged drug and metabolites eliminated from the body via:

> Kidneys: urine

> Hepatobiliary system: fecal elimination

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2
Q

Discuss clearance

A

Clearance (CL) of drug depends on rate of blood flow (Q) through organ and extraction efficiency (E) of organ

> CL = Q x E

> Drug clearance either through liver or kidney

CL = Volume of blood or plasma that is cleared of drug in a given unit of time

  • Units are volumed per time (L/hr)
  • Normalised (L/hr/kg or mL/min/kg)H

Hepatic clearance: CL total = CL renal + CL non-renal

  • Two routes: Metabolism (phase I, phase II) in hepatocytes
  • Excretion in bile
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3
Q

Discuss hepatic enyzmes

A

Enzymes involved in drug metabolism​

  • Many are located in smooth endoplasmic reticulum

> Cytochromes P450 (CYP)

> Glucuronosyltransferases

  • Drug metabolism research can be conducted with hepatic microsomes (vesicles from SER)
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4
Q

What are microsomes

A

a fragment of endoplasmic reticulum and attached ribosomes obtained by the centrifugation of homogenized cells.

> Microsomes can be used to determine the in vitro intrinsic clearance of a compound

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5
Q

What are microsomal enzymes?

A
  • Add substrate (drug) and co-factors to microsomal enzyme suspension
  • Incubate and measure the metabolite formed after specific time (e.g. 30 min) → Plot data
  • Should see increasing amount of metabolite formed as substrate concentration increases

CLint = Vmax / Km

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6
Q

What is intrinsic clearance (CLint)

A

CLint is the “true” measure of enzyme activity

  • Relationship between rate of metabolism and concentration of drug at the enzyme site

CLint = Vmax/Km

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7
Q

Discuss drug metabolism

A
  • Most drugs are metabolized (biotransformed), usually in the liver
  • Phase I reactions introduce or expose a functional group (oxidation, reduction)
  • Phase II involves the addition of groups (conjugation → glucuronidation, sulphation)
  • Metabolites are usually more polar (hydrophilic) & less lipid-soluble than the parent drug → more readily eliminated by the kidney
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8
Q

Describes how drugs change by metabolism, provide some examples

Metabolism ≠ inactivation

A

Inactive prodrugs: activated by metabolism

  • Inactive prodrugs: activated by metabolism
  • Levodopa → dopamine
  • Valaciclovir → aciclovir

Active drugs: active metabolites

  • Aspirin → salicylic acid
  • Codeine → morphine
  • Morphine → morphine-6-glucuronide

Active drugs: toxic metabolites

  • Paracetamol → N-acetyl-p-benzoquinoneimine
  • Pethidine → norpethidine
  • Allopurinol → oxypurinol

Active drugs: inactive metabolites

  • Salicylic acid → salicyl glucuronide
  • Phenytoin → hydroxyphenytoin
  • Morphine → morphine-3-glucuronide
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9
Q

Discuss phase 1 metabolism and cytochrome P450

A

CYP450 system –> hepatic oxidation and reduction

CYPS are a hemoprotein enzymes :

> large protein framework with access channel (entrance) leading to hydrophobic ‘pocket’

> haem lattice structure (iron in Fe2+ state) on the ‘floor’ of the enzyme

  • At least 70 CYP families but on a small proportion dominate in drug metabolism

Major CYP families in human metabolism:

> CYP1A2

> CYP2C9

> CYP2C19

> CYP2D6

> CYP3A4

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10
Q

Discuss phase 2 metabolism

A
  • Usually increase polarity and renal elimination
  • Frequently terminate biological activity
  • “Conjugation” reactions – formation of covalent complexes:

> UDP-glucuronosyltransferases (UGT) –> glucoronidation (morphine, paracetamol)

> Sulphotransferases (ST)

> Glutathione-S-transferases (GST) –> glutathione conjugation

> N-acetyltransferases (NAT) –> acetlylation

  • *ST, GST & NAT are cytosolic enzymes
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11
Q

Discuss glucuronidation

A
  • Usually increases water solubility and changes molecular architecture

> Metabolites generally inactive

  • Metabolites may be eliminated in bile & undergo enterohepatic recycling

> NSAIDs, opioids

  • Role in bilirubin elimination
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12
Q

Discuss EH (hepatic extraction ratio)

A

Q: blood flow through the liver

EH: hepatic extraction ratio

Measures the efficiency of drug removal

  • High Conc of drug OUT –> low EH (–> 0)

​> (fu x CLint) must be >> Q and CL = Q

  • Low Conc of drug OUT –> high EH (–> 1)

> Q must be >> (fu x CLint) and CL = fu x CLint

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13
Q

What happens to hepatic clearance for a low EH drug?

A
  • Increasing fu will increase CL
  • Increased fu will decrease Css
  • Increased fu will not affect CssUNBOUND
  • increasing CLint will increase CL
  • Increased CLint will decrease Css
  • Increased CLint will decrease CssUNBOUND

CL = fu ×CLint

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14
Q

What does dependence of CLhepatic depend on?

A
  • Blood flow (Q) –> the higher the better
  • Intrinsic clearance (CLint) –> the lower the better
  • Protein binding (fu) –> the lower the better
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15
Q

Discuss the first pass effect (absorption effect)

A

The liver is well perfused

After oral dosing –> drug is metabolized before reaching the circulation

  • Typically in the liver, but gut wall metabolism can be significant
  • Bioavailability (F) will be related to the extraction ratio (EH)

F = 1 - EH

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16
Q

What is enterohepatic cycling?

A
  • Drug is excreted in the bile –> either as unchanged drug, or as glucuronide metabolite
  • Drug is re-absorbed from GI tract
  • Glucuronide metabolite is converted by β-glucuronidase enzymes in gut to parent drug, which is re-absorbed
17
Q

Discuss the induction of drug metabolism

A
  • Increased amount of enzyme
  • ↑ Vmax ∴ ↑ CLint
  • Effect is gradual (days to weeks) and reversible (can be slower to reverse)

CL int = Vmax / Km

18
Q

Discuss inhibition of drug metabolism

A
  • No change in amount of enzyme BUT reduced amount of “available” enzyme
  • Non-competitive (block) –> ↓ Vmax ∴ ↓ CLint
  • Competitive (affinity) –> ↑ Km ∴ ↓ CLint (CL int = V max / Km)
  • Effect is rapid (hours) and reversible (prompt on cessation of drug)
  • Inhibition may lead to more profound clinical & toxic effects
19
Q

Provide a summary of drug metabolism (CLint)

A
20
Q

Provide a summary of drug clearance

A
21
Q

Provide a summary of Cl and EH

A
22
Q

Provide a summary for hepatic clearance (protein binding)

A
23
Q

Provide a summary for practical conditions

A
  • First pass effect
  • Enterohepatic cycling
  • Induction of drug metabolism
  • Inhibition of drug metabolism

PK and PA Lectures (11 decks)

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