Metabolism and Excretion

Question 1

Describe the general principles and consequences of drug metabolism.

Answer 1

a. Drug metabolism: drugs undergo enzyme-catalyzed chemical structure transformation after administration to the patient (if only terminated only by renal excretion, the duration of action would be prolonged)
b. Drug metabolizing enzymes have endogenous substrates and play a role in normal metabolism
c. Liver is primary site of drug metabolism, but lungs (30%), intestines (6%), kidney (8%), skin (1%), placenta (5%) and bacteria have enzymes capable of drug metabolism
d. Oxidation is most common pathway, but other types of chemical transformation can occur. Many transformation are catalyzed by membrane-bound enzymes of the SER called CYP450
e. Lipid-soluble compounds are generally converted to more H20-soluble (more polar) compounds that are more readily excreted
f. Generally, metabolism is detoxifying process (active drug to inactive or less active compound), but can also metabolize active drug into MORE active compound (ie: codeine morphine), metabolize inactive compound into active ingredient, metabolize to toxic metabolite

Question 2

Explain the therapeutic consequences of induction

Answer 2

maximal effects seen in 7-10 days, production of pharmacokinetic tolerance (induction by a drug of its own metabolism), induction by 1 agent may increase clearance of another drug reduced therapeutic effect (via increased elimination) or increased toxicity (via toxic metabolite)

Question 3

What is induction

Answer 3

increased drug metabolizing activity (increased clearance) via stimulation of the CYP450 system, compound that causes induction is an “inducer”, mechanism is often increased synthesis of enzyme protein accompanied with increase in liver weight, proliferation of SER, increases in NADPH and cytochrome P450. Requires 48-72 hours to see onset of effect (slow compared to inhibition).

Question 4

Clinically relevant inhibitors

Answer 4

-cimetidine [2D6, 3A4, 1A2]
-erythromycin/cloarithromycin [3A4]
-Azole antifungals [3A4]
-Fluoxetine (other SSRIs) [2D6, 3A4]
-Grapefruit juice [3A4]
HIV protease inhibitors [3A4]
-Omeprazole [2C19]

Question 5

What is inhibition

Answer 5

decrease clearance of drug by inhibiting drug metabolizing activity, phase I enzymes are more prone to inhibition compared to Phase II enzymes. Mechanisms: inhibit enzyme synthesis, inhibitor can act as a substrate competing for the enzyme, inhibitor can be an ihbitor without being a substrate, inhibition results from formation of metabolite that destroys enzyme via covalent bonding or form tight complex with enzymes inhibiting its activity.

Question 6

what are the therapeutic consequences of inhibition?

Answer 6

: inhibition of metabolism can occur as soon as sufficient hepatic concentration is reached (within hours), inhibition by 1 agent of the metabolism of another can result in decreased clearance of the inhibited drug increased toxicity

Question 7

Clinically relevant inducers

Answer 7

• phenobarbital [1A2, 2C9, 2C19, 3A4]
• Phenytoin [2C9, 2C19, 3A4]
• Carbamazepine [2C9, 2C19, 3A4]
• Riphampin [1A2, 2C9, 2C18, 3A4]
• Ethanol [2E1]
• St. John’s Wort [3A4]
• Tobacco smoke [1A2]

Question 8

Excretion:

Answer 8

loss of chemically UNCHANGED drug from the body. Kidneys are MOST important organ for excretion (Especially for water-soluble and non-volatile compounds).

Question 9

Filtration:

Answer 9

glomerular, rate of 120ml/min, all drugs smaller than albumin (MW=69000) will be filtered, only free drug is filtered (NOT protein bound), renal excretion affected by renal blood flow and renal function, drugs cleared by this route have t1/2= 1-4 hours (but high protein binding can extend half-life)

Question 10

Secretion:

Answer 10

active tubule secretion, drugs transported from blood to urine, rate of 120-600 ml/min, occurs with drugs that are stronger acids and bases in proximal tubule via secretory mechanism that are saturable (examples of drug substrates for transporter= acids: penicillins, salicylate, diuretics, bases: morphine, catecholamines, histamine), plasma protein binding (reversible) does NOT appreciably affect rate of secretion (t1/2= 1-2 hours), poorly developed process in neonates (therefore prolonged half- lives).

Question 11

Tubular Reabsorption:

Answer 11

drugs that are lipid-soluble and uncharged WOULD be cleared at rate of urine formation (1 ml/min) but the primary function of drug metabolism is to produce more water soluble metabolite that is less likely to be reabsorbed. In order to be reabsorbed, drugs must pass through membranes.

Question 12

Passive diffusion occurs

Answer 12

with lipid soluble molecules in proximal and distal tubules, as water is reabsorbed, lumen to blood back-diffusion is favored as drug is concentrated in luminal fluid.

Question 13

Diffusion of weak acid/bases dependent upon urine pH (non-ionized form only will diffuse across membrane), can

Answer 13

change urinary pH with NH4Cl (acidify) or NaHCO3 (alkalinize)

Question 14

Active reabsorption is particularly important for

Answer 14

endogenous compounds (glucose, aa’s), most drugs REDUCE this active transport