1-44 Drug Elimination

Question 1

Drug elimination (percentages)

Answer 1

Question 2

Liver metabolism scheme overview

Answer 2

Question 3

Clearance

Answer 3

• rate at which a substasnce is removed from plasma per unit concentration
• reflects hypothetical volume of plasma that is completely cleared of the substance per unit time
• volume of plasma that is cleared is related to the efficiency of elimination: the greater the rate of elimination per unit concentration in plasma, the higher the clearance
• clearance = elimination rate / plasma drug concentration (units volume/time)
  
  • ​summation of clearance from each organ to get total clearance from plasma

Question 4

Renal drug excretion (3 routes overview)

Answer 4

1. Glomerular filtration: only happens at glomerulus
   
   • unbound drugs (water or lipid soluble) are feely filtered
   • protein bound drugs not filtered
   • excretion is proportional to glomerular filtration rate (GFR) and free drug concentration i nthe plasma
     
     • normal GFR: 125 ml/min (180 L/day)
     • for drugs only exreted by glomerular filtration, elimination = GFR x [free drug]
   • drug dosing should be modified in GFR is low (kidney failure, old people)
   • drugs that are eliminated primarily by renal mechs should be closely monitored for dosing in GFR comprimised pts
2. Tubular reabsorption (competes with mechanisms 1 and 3): occurs along whole length of renal tubule, passive
   
   • filtered lipid-soluble and other non-ionized drugs can be reabsorbed beyond the proximal tubule
   • reabsorption occurs by diffusion or transporters
   • ionized drugs/metabolites are not effectively reabsorbed
   • reabsorption of lipid solube drugs contiabutes to their longer half-life in body
   • reabsorption is impaired by high flow rates (diuresis)
   • tubular fluid pH may promote or impair reabsorp
     
     • could trap in ionized form and prevent reabsorption and promote excretion
3. Tubular secretion: happens at specific segements of renal tubule (proximal tubule)
   
   • ionized form of drugs are transported by cellular route
   • both ABC and SLC transporters are involved
     
     • Organic cation transporters (OCTs) for weak bases
     • Organic anion tranposrters (OATs) for weak acids
     • multidrug and toxin extrusion protein (MATE)
     • MDR1 (p=glycoprotein) and MRP proteins
   • Free drug can be secreted; in equilibirum with protein-bound drug

• leaky endothelium: under pressure, fluid is pressed through the fenestrations (cells too big, plasma proteins like albumin too big) and small molecules can be filtered (charge effects filtration)

Question 5

Effect of molecular size and charge on Glomerular filtration

Answer 5

• larger, less filterable
• more negative charge, less filterable

Important: many proteins/drugs get bound to albumin/other similar proteins and this would prevent them from being filtered by the kidney

Question 6

Renal drug excretion: tubular secretion

Answer 6

Question 7

Effect of pH on renal drug excretion

Answer 7

• ionized form of drug has greater ability to excrete
• neutral form of drug is prone to reabsorption in kidney

Question 8

Hepatic Clearnace

Answer 8

• Hepatic Clearance (Clh) is calculated by the product of hepatic blood flow (Qh) times the extraction ratio (E): Clh = Qh x E
• Extraction ratio (E) = (Cin – Cout) / Cin, whereas
  
  • Cin = concentration of drug in portal vein
  • Cout = concentration of drug in hepatic vein
• High extraction drugs (E > 0.7) are ‘flow limited’
• Low extraction drugs (E < 0.3) are limited by intrinsic hepatic metabolic capacity and fraction of free drug (unbound to protein)

Question 9

Biliary Drug Excretion

Answer 9

• Transfer of drug or drug metabolites from the plasma to the bile through the hepatocytes.
• Drugs handled by biliary excretion are eliminated in feces.
• Drugs may be excreted into the bile either in a native form or after metabolism into more polar conjugates.
• Bile is released in the gut lumen, from which the native drug can be reabsorbed (enterohepatic cycle).
• Conjugated drugs can be liberated by intestinal bacteria and also reabsorbed.

Question 10

Bile drug excretion close up look

Answer 10

Question 11

Enterohepatic circulation/cycle

Answer 11

• drugs conjugated in the liver to form glucornides are secreted into the bile
• can be cleaved by bacterial Beta-glucuronidases in the colon to liverate teh drug molecule, which is then reabsorbed
• creates a reserboir of 20% of total drug i nthe body, can prolong drug half-life
• Recycles drug
  
  • if you wipe out intestinal bacteria (via antibiotics) you will affect the dosing/therapuetic intent of some drugs that rely on this recycling

Question 12

Renal drug excretion: Glomerular filtration

Answer 12

1. Glomerular filtration: only happens at glomerulus
   
   • unbound drugs (water or lipid soluble) are feely filtered
   • protein bound drugs not filtered
   • excretion is proportional to glomerular filtration rate (GFR) and free drug concentration i nthe plasma
     
     • normal GFR: 125 ml/min (180 L/day)
     • for drugs only exreted by glomerular filtration, elimination = GFR x [free drug]
   • drug dosing should be modified in GFR is low (kidney failure, old people)
   • drugs that are eliminated primarily by renal mechs should be closely monitored for dosing in GFR comprimised pts

Question 13

Renal drug excretion: Tubular Reabsorption

Answer 13

1. Tubular reabsorption (competes with mechanisms 1 and 3): occurs along whole length of renal tubule, passive
   
   • filtered lipid-soluble and other non-ionized drugs can be reabsorbed beyond the proximal tubule
   • reabsorption occurs by diffusion or transporters
   • ionized drugs/metabolites are not effectively reabsorbed
   • reabsorption of lipid solube drugs contiabutes to their longer half-life in body
   • reabsorption is impaired by high flow rates (diuresis)
   • tubular fluid pH may promote or impair reabsorp
     
     • could trap in ionized form and prevent reabsorption and promote excretion

Question 14

Renal drug excretion: Tubular secretion

Answer 14

1. Tubular secretion: happens at specific segements of renal tubule (proximal tubule)
   
   • ionized form of drugs are transported by cellular route
   • both ABC and SLC transporters are involved
     
     • Basolateral side: faces capillary
       
       • SLC22 family: majority uptake of ionized drugs from plasma into the cells lining the proximal tubule
     • Apical side: lumen facing
       
       • Organic cation transporters (OCTs) for weak bases
       • Organic anion tranposrters (OATs) for weak acids
       • multidrug and toxin extrusion protein (MATE)
       • p-glycoprotein: ampipathic anions
       • MRP proteins: secrete cojugated metabolites (glucuronide adducts)
   • Free drug can be secreted; in equilibirum with protein-bound drug
   • SLC system relatively non-selective so there can be competition and drug-drug interactions to get reabsorbed

• leaky endothelium: under pressure, fluid is pressed through the fenestrations (cells too big, plasma proteins like albumin too big) and small molecules can be filtered (charge effects filtration)

Question 15

Glomerular filtration structure

Answer 15

• acts as blood filter
• 3 layers of membranes
  
  1. glomerular capillary endothelium: fenestrated
  2. glomerular basement membrane: porous
  3. podocytes: interdigitating foot processes with filtration slits
• endothelial and podocytes: many negatively charged glycoproteins, helps attract size and charge specific solutes to filter
  
  • large neatively charged proteins not filtered