Pharmacokinetics of Excretion

Pharmacokinetics

Excretion: Exit of the drug and its metabolites

1. Main routes:
   1. Kidneys (Urine): Active (ATPase pumps) or Passively
   2. Liver
   3. Bile: Possibility for enterohepatic recirculation
      1. Bile > Duodenum > Reabsorption in the small intestine > Portal circulation > Liver (Metabolism) > Bile > Repeat
         1. Extensive enterohepatic recirculation for: Diazepam, Morphine, Metronidazole (In Dogs and Horses), Albendazole (In Ruminants)
            1. Bile content ends up in the intestine and gest mixed to the feces
2. Subsidiary routes:
   1. Milk: Drugs that have a Withdrawal Period for the milk
   2. Sweat
   3. Tear
   4. Breath: Volatile drugs (Volatile oils, Inhalation Anesthetics)

Total body clearance: Cl b

1. The volume of plasma cleared of a drug over a specified time period
   1. Ex: In 1h we have totally have removed 50% of the drug from a total plasma volume of 5L = In 1h we have totally removed the drug from 2.5L of plasma = The Total body clearance Cl b = 2.5 L / h = 41.67 mL / min
2. It is equal to the sum of Renal Clearance Cl r and Metabolic clearance Cl m
   1. Cl b = Cl r + Cl m = Dose / Area Under the Curve AUC
   2. If no metabolism occurs: Cl r = Ke (Elimination rate) x Vd (Volume of distribution)
   3. If the liver metabolism is maximal: Cl m = Km (Metabolic rate) x Vd (Volume of distribution)

Renal excretion:

1. Net Renal Excretion: Sum of the Filtration, Reabsorption and Secretion processes
   1. Filtration: Passive transport of the drug from the blood to the urine, in the glomerulus
   2. Reabsorption: Passive transport of the drug from the urine back to the blood. May be affected by alterations of the urinary pH (Ion trap)
      1. Ion trap: An molecule changing milieu (Ex from blood to urine > Change of pH) and becoming ionized can’t diffuse back through the lipid membrane because the ionization made it lipophobic
      2. At low urine pH: Basic drugs are less reabsorbed (Because they are) protonated and ionized > More excreted
         1. Ex: Local Anesthetics, SedatoHypnotics, Bronchodilators
      3. At high urine pH: Acidic drugs are less reabsorbed (Because they are) deprotonated and ionized > More excreted
         1. Ex: Penicillins, Sulfonamides, Phenylbutazone (In Horses)
   3. Secretion: Active transport (By OATs, OCTs) of the drug from the blood to the urine, in the tubule

Hepatic excretion of drugs:

1. Excretion of the parent drug and its metabolites in the bile
2. Used for excreting bigger molecules than the Kidney’s (>600 Da)
3. Involves the same transporters for acidic and basic drugs
4. Large organ (3% of BW) with high perfusion rate (27% of the Cardiac Output)
5. High metabolic activity (Pharmacokinetics of Metabolism) which influences the Oral Bioavailability of drugs through the First Pass effect (Pharmacokinetics of Absorption)
6. Can be involved in Enterohepatic Recirculation (Pharmacokinetics of Absorption)

Drug-drug interaction can occur on a Excretion level:

1. In the Kidney:
   1. Organic Anion Transporter OAT:
      1. Secretes: Penicillins-G, Methotrexate, Furosemide
      2. Inhibited by: Probenecid, NSAIDs
      3. Effect: Decreased secretion > Increased concentration, activity and toxicity
   2. Organic Cation Transporter OCT:
      1. Secrete: Lamivudine, Procainamide, Metformin
      2. Inhibited by: Trimethoprim, Cimetidine
      3. Effect: Decreased secretion > Increased concentration, activity and toxicity
   3. ATP Binding Cassette B1 ABCB1:
      1. Secrete: Digoxin
      2. Inhibited by: Quinidine
      3. Effect: Digoxin toxicity due to increased concentration

Factors influencing drug excretion:

1. Age: Excretion less active in newborn and aged animals
2. Other drugs: Drug-drug interactions
3. Diseases: Kidney and Liver insufficiency significantly decrease the clearance (Slower elimination)