PK 07: Clearance – Physiological Concepts

Question 1

Where does drug metabolism occur?

Answer 1

• primarily in the liver
• also in small intestine, kidney, lung

Question 2

What is phase I of drug metabolism?

Answer 2

oxidation, reduction, hydrolysis

• introduces or unmasks polar functional groups such as –OH (hydroxyl), NH2 (amino), or –SH (sulfhydryl) that may be subject to phase 2 metabolism
• facilitated by the presence of drug metabolizing enzymes called cytochrome P450 enzymes (CYPs)

Question 3

What is phase II of drug metabolism?

Answer 3

glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione, and conjugation with amino acids

• addition of an endogenous hydrophilic group to form a larger, polar, water-soluble, inactive metabolite that is easier to excrete
• normally follows phase I metabolism, but can occur independently
• facilitated by mainly UDP-glucuronosyltransferases (UGT1 and UGT2), but also sulfotransferases (SULTs), N-acetyltransferases (NATs), glutathione S-transferases (GULTs), methyltransferases

Question 4

What is the major route for drug excretion?

Answer 4

urine (kidney)

• polar, water-soluble non-volatile, and unbound compounds undergo renal excretion
• mechanisms of renal drug clearance: glomerular filtration (passive), tubular secretion (active), tubular reabsorption (active/passive)

Question 5

What are the minor routes for drug excretion?

Answer 5

• bile (liver)
• exhalation
• sweat
• lactation

Question 6

Describe the bile (liver) route for drug excretion.

Answer 6

• active transport
• excreted drugs are polar (hydrophilic) and MW > 350 g/mol
• excreted drugs entering GI tract can be excreted via feces or reabsorbed via enterohepatic circulation

Question 7

Estimating Total Body Clearance

Answer 7

assume blood clearance is equivalent to plasma clearance

Question 8

What is fe?

Answer 8

fraction of drug excreted unchanged in the urine

Question 9

What is 1-fe?

Answer 9

fraction of drug eliminated by other processes – usually assumed to be the fraction of drug metabolized (fm)

Question 10

What is the shortcut for evaluating fe and renal vs. hepatic clearance?

Answer 10

• fe > 0.5: renal clearance more important
• fe < 0.5: hepatic clearance more important
• fe = 0.5: hepatic and renal clearance equally as important

Question 11

What is the organ-specific extraction ratio (E)?

Answer 11

fraction of drug presented to the organ that is eliminated during one pass

• drugs are categorized based on efficiency of the organ at eliminating the drug

Question 12

What is the E for a high E drug?

Answer 12

> 0.7

Question 13

What is the E for a low E drug?

Answer 13

< 0.3

Question 14

What is the E for a moderate E drug?

Answer 14

0.3-0.7

Question 15

What is linear PK?

Answer 15

rates of drug absorption, distribution, and elimination are governed by first-order processes – rates are directly proportional to the amount/concentration of drug present

• dose-independent
• time-independent

Question 16

Describe how PK parameters change with linear PK.

Answer 16

PK parameters (CL, V, t1/2) remain constant

Question 17

What is non-linear PK?

Answer 17

rates of drug absorption, distribution, and elimination are governed by non-linear processes – rates are not directly proportional to the amount/concentration of drug present

• dose-dependent
• time-dependent

Question 18

Describe how PK parameters change with non-linear PK.

Answer 18

PK parameters change with dose or time

Question 19

What are the causes of non-linear PK?

Answer 19

saturation of one or more of the key PK processes

• saturable metabolism (most common – see below)
• saturable excretory transport
• saturable plasma protein or tissue-binding
• saturable absorption
• saturable first-pass

time-dependent changes in PK parameters

• auto-induction
• auto-inhibition

Question 20

When does saturation of metabolic clearance occur?

Answer 20

occurs at high drug concentrations when capacity of eliminating enzyme system is overwhelmed (ie. saturation)

• enzyme system is functioning at or near its maximum capacity (capacity-limited metabolism)

Question 21

What is the Michalis-Menten model?

Answer 21

describes enzyme-specific drug metabolism in-vitro

• can also be applied to describe in-vivo drug metabolism

Question 22

What is the effect of metabolic saturation on half-life (t1/2)?

Answer 22

increases t1/2