Drug Absorption and Metabolism

Drug Absorption

• Describes drug movement from the administration site into systemic circulation
• LogP indicates drug solubility
  • A positive LogP signifies lipophilic properties
  • An equal LogP signifies hydrophilic properties
• Prodrugs are lipophilic substances with little to no activity that are metabolized into an active form
• Intestinal ABC transporters include MDR1, MRP2, and BCRP
• ER (efflux ratio) > 2 indicates efflux

Drug Metabolism

• Lipophilic drugs yield more metabolites than hydrophilic drugs
• Oxidation is one type of Phase 1 metabolism
  • Ethanol becomes acetaldehyde through alcohol dehydrogenase (ADH)
• Hydrolysation is another type of Phase 1 metabolism and involves prodrugs
  • Tenofovir disoproxil is converted to tenofovir via esterase
  • Tenofovir is not the pharmacologically active metabolite
• Dealkylation
  • Codeine is converted to morphine via CYP2D6 during Phase 1 metabolism
• Phase 2 metabolism involves metabolites transforming into more metabolites
  • This increases the drug's water solubility for renal excretion
• Glucuronidation is a process in Phase 2 metabolism
  • Morphine-3-glucuronide (inactive)
  • Morphine-6-glucuronide (active)
• Sulfation
  • SULT (sulfotransferase)
• Glutathione conjugation detoxifies NAPQI
• Some drugs can skip Phase 1 metabolism
• Glutathione conjugation eliminates NAPQI
  • Glutathione depletion increases toxicity
• Metabolism increases molecular size, reducing distribution
• Metabolism lowers the half-life (t1/2)
• Metabolism makes drugs more hydrophilic, facilitating renal excretion
• Phase 1 drugs are typically lipophilic
  • They convert to hydrophilic forms through hepatic metabolism
  • Then are excreted in bile or urine
• Phase 2 drugs are hydrophilic and undergo renal excretion
• Examples of metabolites:
  • Inactive: Morphine-3-glucuronide
  • Active: Morphine-6-glucuronide
  • Active & toxic: NAPQI
• Prodrug example: codeine converts to morphine
• CYP3A4 is the most important drug-metabolizing enzyme (DME) due to its broad substrate specificity
• CYP2D6 is the most polymorphic DME and metabolizes codeine into morphine
• CYP2E1 metabolizes paracetamol into NAPQI and ethanol into acetaldehyde
• CYP enzymes can undergo inhibition or induction
• Rifampicin induces CYP3A4
  • This increases midazolam metabolism to 1-hydroxymidazolam
  • Decreases plasma concentration
• Itraconazole inhibits CYP3A4
  • This decreases midazolam metabolism
  • Increases plasma concentration
• Acute drinkers:
  • Ethanol and paracetamol compete for CYP2E1, resulting in less NAPQI production
  • This leads to a low risk of toxicity
• Chronic drinkers:
  • Ethanol induces CYP2E1, increasing NAPQI production
  • This leads to an increased risk of toxicity
• Ritonavir, cobicistat, and itraconazole are CYP3A4 inhibitors
• Probenecid inhibits Organic Anion Transporter (OAT) 1/3
• Rifampicin is a CYP3A4 inducer

Drug Excretion

• Involves the physical removal of the drug
• Elimination is the combined process of metabolism and excretion
• fu is the fraction of unbound drug in plasma
  • High fu signifies more free drug in plasma, increasing therapeutic effect
  • Low fu signifies more drug bound to plasma proteins, delaying therapeutic effect
• Increased creatinine in the blood indicates impaired renal function
• Sodium bicarbonate treats aspirin overdose by reducing absorption
  • It increases salicylic acid ionization by raising pH (making it more basic)
• Probenecid is an OAT1/3 transporter inhibitor
  • It enhances cephaxelin levels
• Breast milk has a low (acidic) pH
  • Basic and small lipophilic drugs can passively diffuse into breast milk
• Codeine metabolizing into morphine in an ultrarapid metabolizer mother causes breast milk excretion & toxicity in infant
• fe is the fraction of drug excreted unchanged
  • High fe indicates excretion of the parent drug with little metabolism
  • Low fe signifies the drug is metabolized
• F is bioavailability, defined as the fraction of the dose that reaches systemic circulation
  • For IV drugs, F = 100%

Quantitative Pharmacokinetics

• Cmax in IV administration begins at time T=0 on a concentration/time curve
• Therapeutic window is the range between the minimum effective concentration (MEC) and the maximum tolerated concentration (MTC)
• First order kinetics involves a change in concentration by a constant factor over time and involves t1/2
  • Most drugs follow this
• Zero order kinetics involves a change in concentration by a constant amount over time
  • Ethanol follows this and can change to first order
• Ethanol eliminated by ADH
• Steady state concentration is achieved when the rate of absorption equals the rate of elimination

Drug Action

• Only bound drugs cause effects
• Increasing the loading dose increases receptor activation and response
• K+1 >>> K-1 signifies high force of attraction, thus high affinity