Drug Metabolism and Elimination

Question 1

Characteristics of Enzyme-Catalyzed Reactions

Answer 1

*Reaction Rate is Proportional to the level of Drug when at Low Drug Concentrations.
==> Concentration-Dependent
(First-Order Kinetics)

Reaction Rate is Independent of Drug levels when at High Drug Concentrations and with Constant amounts of the Enzyme.
(Zero-Order Kinetics)

*The Maximum Reaction Rate occurs when the Enzyme is Saturated.
(Zero-Order Kinetics)

Question 2

Tissue Locations of Drug Metabolism

Answer 2

*Liver: *Quantitatively Most Important Site for Most Drugs.

*GI Tract: often a component of “First Pass metabolism)
(also, p-glycoprotein, a carrier protein in the GI, pumps drugs back into the lumen that are recognized as foreign, inhibiting absorption)

*Lungs and Nasal Mucosa: Metabolize inhaled toxins. Protect body against inhaled toxins.

Kidney: high drug metabolizing activity, but is a small organ.

Question 3

Cellular Locations of Drug Metabolizing Enzymes

Answer 3

• Plasma: Hydrolysis
• Mitochondria: Oxidation, Reduction

**Endoplasmic Reticulum or **Microsomes: Oxidation, Glucuronidation

*Cytosol: Conjugation, Reduction, Hydrolysis

Question 4

Types of Drug Metabolism Reactions:

Phase I

Answer 4

Phase I (Non-synthetic) Reactions *form Active, Inactive, and/or Chemically Reactive metabolites.

1) Hydrolysis of Esters and Amides.
2) Oxidation (Microsomal Mixed Function Oxidase) System:

–Main enzyme: *Cytochrome P450,

–Cytochrome P450 is a *Microsomal Heme Protein with Multiple Forms:
*2C9, *2D6, *3A4
(3 most important forms)

(Heme protein means contains iron)

CYP450 is an *Inducible enzyme.
–Drugs can induce it, causing increased activity of the enzyme.

–Other required components: *Microsomal NADPH Cyt P450 Reductase.

*Overall Reaction:
Drug + NADPH + O2 + H+
–>
Oxidized Drug + H2O + NADP+

–3 Main Oxidation Reactions we will discuss:
Dealkylation (removal of a methyl group), Primary amine oxidation, and Deamination.

Question 5

Types of Drug Metabolism Reactions:

Phase II

Answer 5

Phase II (Synthetic) Reactions: form Inactive Metabolites (almost always) that are readily excreted.
(Synthetic/Conjugation Rxns)

1) Glucuronide Synthesis:
- -Major Route,
- -Many drugs with -OH groups.

a) UDP-glucuronic acid (UDPG) is the *glucuronide group donor.

b) Enzyme is Glucuronyltransferase, a *Microsomal enzyme.
- —Inducible
- —Low in Neonates

2) Acetylation
3) Glycine Conjugation

4) Methylation:
*O-, N-, and S-Methyltransferases.
*S-Adenosylmethionine (SAM):
is the methyl donor for Methylation.
e.g. norepinephrine –> epinephrine

5) Sulfation

6) Mercapturic Acid Formation:
==> *Glutathione Conjugation.
–Acetaminophen (Tylenol) is metabolized to Sulfate (45-50%) and to Glucuronide (45-50%).
–Glucuronide and sulfate metabolites are non-toxic.
–4-5% of it may be metabolized to an Oxidative metabolite (toxic) (reactive oxygen form, specifically a free radical form).
–Oxidative metabolite (toxic) undergoes *Glutathione conjugation, forming Mercapturic Acid metabolite (non-toxic)
–At low doses of tylenol, there is enough Glutathione enzyme available in the liver.
–At high doses of tylenol or in the presence of an inducer of the enzyme (such as alcohol, which has high p450 activity), *Glutathione Depletion results in *Metabolite-induced injury.

**Acetaminophen Toxicity

**N-acetylcysteine (Mucomyst) reduces liver damage by increasing biosynthesis of Glutathione and scavenging free radicals.

Question 6

Factors Influencing Drug Metabolism

Answer 6

1) Enzyme Induction:
- -Relatively *Slow Increase (days-weeks) in the Rate of Drug Metabolism.

–> *Accelerates Drug Clearance = *Increased Drug Metabolism, Reducing Duration of Drug Action.

2) Enzyme Inhibition:
- -*Rapid Decrease (min-hours) in Rate of Drug Metabolism.

–> *Decreases Drug Clearance (Deactivation), Prolonging Duration of Action

3) Age:
–*Metabolism Depressed in Infants and Elderly
*(Oxidative depressed more than Conjugation in Elderly) (So Phase II is better for Elderly than Phase I)
(Neonates have low Glucuronyltransferase, so Phase I is better for Infants than Phase II)

4) Liver Disease (Cirrhosis, Hepatitis):
- -*Decreases Drug Metabolism.

5) Genetic Variation:
- -*More individualized Drug therapy, according to gene analysis.
- -may lead to increased or decreased drug activity.

Question 7

Drug Excretion (Elimination)

Answer 7

*Occurs by a Reverse process of Distribution and Absorption.

–Any medium (urine, bile, feces, expired air, etc.) produced by tissues (kidney, liver, intestine, lung, etc.) with access to the external environment represents a potential route of drug elimination.

Question 8

Drug Clearance

Answer 8

Expressed as a Volume per unit of time (L/hr).

Represents the *Apparent (not the actual) volume of plasma or blood that is cleared of the drug in a given period of time.

Question 9

Renal Elimination

Answer 9

Most drugs are excreted via kidney. Most important route.

Either “Parent” Drug or Metabolite

1) Tubular Secretion (Proximal Tubule):
- -Increases Drug Clearance
- -Organic Acid Transport (OAT) System: Specific for Acids
- -Competition for carriers occurs within specific system; potential for drug interactions.
- -Protein-bound drugs (in plasma) are readily secreted.

2) Tubular Reabsorption:
- -Drum moves from lumen back into Blood.
- -Passive diffusion is primary route of drug uptake; depends on Concentration and Lipid Solubility (Ionization)
- -> Ionized form of drug stays in tubule; Nonionized form can cross lipid membrane back into blood.
- -Ionization: *Acid excretion is increased by NaHCO3 (alkalinizes urine); Base excretion is increased by NH4Cl (acidifies urine)

3) Glomerular Filtration results in a protein-free blood filtrate.
- -Capillaries are permeable to most Non-protein-bound drugs.
- -*Non-saturable process (first-order kinetics)

Question 10

Interpretation of Renal Clearance

Answer 10

Renal clearance = volume of plasma cleared of drug /min or hr

Creatinine Clearance is a lab measure of GFR
(This is because creatinine is not secreted by tubular carrier mechanism and is not reabsorbed; thus, what is filtered through the glomerulus is eliminated in the urine)

*Interpretation:

–If Clearance > GFR, indicates Tubular Secretion

–If Clearance is Less Than GFR, indicates Tubular Reabsorption

–If Clearance = GFR, indicates Neither Net Secretion Nor Reabsorption

Question 11

Factors Reducing Renal Clearance of Drugs

Answer 11

*May need to Reduce Dose or Increase Dosing Interval.

–*Infants and *Elderly

–*15-20% Less in Women than Men

–*Kidney Disease and Heart Disease

–Competition for Carriers (Drug Interaction)

Note: *Dialysis Increases Drug Clearance; used in kidney failure and in some drug overdose.

Question 12

Liver Excretion of Drugs

Answer 12

Liver is second most important route of excretion.

1) Hepatic Uptake of Circulating Drugs:

–*Portal Circulation: brings drugs from GI tract to Liver

–High Extraction Ratio drugs are readily deactivated as they pass through the liver –First Pass

–*Transport Proteins enhance uptake by the liver; content induced by drugs

–*Drug Metabolites are secreted into bile.

2) Enterohepatic Cycle:
(Liver –> Common Bile Duct –> Small Intestine –> Superior Mesenteric Vein –> Portal Vein –> Liver)

–*Active secretion of drug and/or metabolites.

–*Hydrolysis (beta-glucuronidase) of drug metabolites in intestine.

–*Prolonged Duration of Drug Response.

Question 13

Other Routes of Drug Excretion

Answer 13

GI: some oral drugs that are not absorbed, acting within GI tract.

*Pulmonary Excretion of Gaseous and Volatile Drugs

Mammary Glands (Breast Milk):

• -Passive Diffusion
• -Potential Ion Trapping
• -*Infant Exposure: *Toxicity, *Dependence

*Sweat Glands