Lecture 4 to 5: PK

Question 1

ENTERAL ROUTES

Answer 1

• Oral
• Sublingual: bypasses first-pass effect
• Rectal: partial avoidance of first-pass effect

Question 2

PARENTERAL ROUTES

Answer 2

• IV
• IM
• Sub-Q
• Intradermal

Question 3

EFFECT OF pH ON DRUG ABSORPTION

Answer 3

• The protonated form of a weak acid is the more liposoluble form
• The unprotonated form of a weak base is the more liposoluble form.

Question 4

APPLICATIONS OF THE H-H EQUATION

Answer 4

ION TRAPPING

• The most important application of this equation is in the manipulation of drug excretion by the kidney.
• If a drug is in a liposoluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by passive diffusion.
• Weak acids are excreted faster in alkaline urine; weak bases are excreted faster in acidic urine.

Question 5

DETERMINATION OF BIOAVAILABILITY (F)

Answer 5

determined comparing the AUC after a particular route of administration with the AUC after IV injection.

Question 6

FACTORS THAT INFLUENCE BIOAVAILABILITY

Answer 6

• DRUG FORMULATION
• CHEMICAL INSTABILITY
• FOOD AND DRUG INTERACTIONS
• FIRST-PASS HEPATIC METABOLISM
• DRUG SOLUBILITY
• P-GLYCOPROTEIN

Question 7

DRUG DISTRIBUTION

Answer 7

• Initially, liver, kidney, brain, and other well- perfused organs receive most of the drug.
• Delivery to muscle, most viscera, skin, and fat is slower.

Question 8

DRUG BINDING TO PLASMA PROTEINS

Answer 8

• Acidic drugs bind to plasma albumin and basic drugs to α1-acid glycoprotein.
• Drugs can compete with each other and with endogenous substances for these binding sites.
• Displacement of unconjugated bilirubin from albumin by sulfonamides increases the risk of bilirubin encephalopathy in the newborn, i.e. Sulfonamide admin in mother or newborn causes kernicterus
• drugs with a narrow TI, a transient change in the unbound concentration due to administration of a competing drug could be of concern.
• Warfarin is highly bound to albumin and only a small fraction is free.
• If a sulfonamide is given, it will displace warfarin causing a significant increase in the plasma level of free warfarin.

Question 9

BLOOD-BRAIN BARRIER

Answer 9

• only liposoluble drugs can cross the bbb.
• transcellular route

Question 10

DRUG METABOLISM

Answer 10

• Many drugs are lipophilic
• But lipophilic compounds are not easily excreted because they are reabsorbed through the tubular membranes.
• Drug metabolism involves two kinds of biochemical reactions:
  • phase I: ER & cytosol
  • phase II: cytosol

Question 11

PHASE I REACTIONS

Answer 11

• oxidations, reductions, decarboxylations, deaminations and hydrolytic reactions.
• usually convert the parent drug to a more polar metabolite
• In some instances activity is only modified or even enhanced.

Question 12

PRODRUGS

Answer 12

One example is the drug cyclophosphamide, which is bioactivated by metabolism to an active anticancer metabolite

Question 13

PHASE II REACTIONS

Answer 13

• conjugation reactions form a covalent bond between the drug molecule and glucuronate, acetate, glutathione, amino acids or sulfate.
• Not all drugs undergo these sequential reactions (Phase I → Phase II).
• Ex. isoniazid is acetylated by N-acetyltransferase, in a phase II reaction.
• The acetylated conjugate then undergoes a phase I reaction: hydrolysis to isonicotinic acid.

Question 14

SITES OF DRUG METABOLISM

Answer 14

• Liver: most imp
• skin, the lungs, the GI tract, and the kidneys.

Question 15

ENZYME INDUCTION

Answer 15

• Certain drugs increase the synthesis of one or more P450 isoforms such as
  
  • **phenobarbital: **benzo
  • **rifampin: **antimycobacterial
  • carbamazepine: anti-epileptic
• St. John’s wort increases the metabolismof various drugs, by inducing CYP3A4.
  
  • Ex. St. John’s Worts co-admin decreases levels of Indinavir, an anti-HIV drug/protease inhibitor

Question 16

XENOBIOTIC RECEPTORS

Answer 16

• Drugs can enter hepatocytes and bind to xenobiotic receptors.
• This activates the receptor, allowing it to translocate to the nucleus and bind to the promoters of various enzymes.
• Aryl hydrocarbon receptor(AhR)
• Pregnane X receptor (PXR)
  
  • Note: Hyperforin in St. John’s Worts in the tabl
• Constitutively active receptor(CAR)

Question 17

CYP ENZYME INHIBITION

Answer 17

• Amiodarone: ANTIARRHYTHMICS Class III
• Cimetidine: H2 Antagonists
• Ketoconazole: anti-fungal
• Erythromycin: macrolide
• Chloramphenicol: antimicrobials
• Grapefruit juice: inhibits both CYP3A4 and P-glycoprotein in the small intestine

Question 18

DRUG TRANSPORT

Answer 18

• P-glycoproteinactively transports drugs back into the intestinal lumen.
• This process limits the oral bioavailability of several drugs, including digoxin and HIV-1 protease inhibitors.
• Drug transporters can be induced or inhibited by other drugs.
• For example, macrolide antibiotics, Ex. Clarithomycin, can inhibit P-glycoprotein.
• This inhibition can lead to increased serum levels of drugs, such as digoxin, that are excreted by P-glycoprotein.

Question 19

DRUG TRANSPORT: INDUCTION & INHIBITION

Answer 19

• P-glycoprotein is also transcriptionally regulated by PXR.
• So, drugs that induce P450 enzymes via the PXR pathway also induce P-glycoprotein.

Question 20

METABOLISM OF ACETAMINOPHEN

Answer 20

• Acetaminophen metabolises in 3 ways:
  
  • Glucoronate
  • Sulfonate
  • NAPQI (minor, 5%):
    
    • CYP2E1 catalyzes
    • normally have enough GSH to detoxify the NAPQI levels
• antidote is N-acetylcysteine when NAPQI is high
• It supplies cysteine for glutathione production, and also reacts directly with NAPQI.

Question 21

EFFECT OF GRAPEFRUIT ON FELODIPINE METABOLISM

Answer 21

• Felodipine: Ca2+ channel blocker
• Grapefruit juice inhibits CYP3A4 -> incr. serum felodipine levels

Question 22

DIET & ENVIRONMENTAL FACTORS

Answer 22

• Aromatic hydrocarbons in cigarette smoke cause AhR-mediated P450 enzyme induction.
• Charcoal-broiled foods and cruciferous vegetables induce CYP1A enzymes.
• Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than nonexposed individuals.

Question 23

DRUG EXCRETION

Answer 23

• Renal excretion is the most common mechanism of drug excretion.
• A small number of drugs are excreted in the bile.

Question 24

RENAL EXCRETION OF DRUGS & METABOLITES

Answer 24

3 basicprocesses involved in renal excretion of drugs:

1. Glomerular filtration

• Glomerular capillaries allow drug molecules of MW < 20,000 to diffuse into the glomerular filtrate.
• Lipid solubility and pH don’t influence the passage of drugs into the glomerular filtrate.

2. Active tubular secretion: drug molecules are pumped into the lumen of the tubule by two active transport systems: one for anions and one for cations.
3. Passive diffusion across tubular epithelium: Liposoluble drugs can be passively reabsorbed.