7-8. drug elimination & ADME in special populations

how is drug elimination measured?

clearance = volume of plasma from which a drug is completely removed / time

what are the routes of drug elimination?

• renal (major route)

• hepatic (second most important route)

• other body fluids (milk, sweat, expired air, tears; minor routes)

what is renal clearance? (CL_r)

• volume of plasma from which a drug is completely removed by the kidney over a given time interval

• influenced by amount of drug filtered, secreted, and resorbed

what properties influence how easily drugs get through the filtration barrier?

• size: solutes with MW < 50 kD are easily filtered

• shape: flexibility & deformability ease filtration

• charge: cationic solutes filter more easily anionic

• F_x: fraction of a substance not bound to plasma proteins

i.e. low molecular weight, unbound drugs are filtered; the rest remain in blood

glomerular filtration of drugs

• not transporter-mediated and is NOT saturable

• dependent on glomerular filtration rate (GFR)

what types of drugs are actively secreted?

• weak acids (organic anions)

• weak bases (organic cations)

• poorly filtered drugs (due to charge, size, or binding to plasma proteins)

tubular reabsorption of drugs

• as water is reabsorbed from urine, lipophilic drugs passively diffuse through distal tubule & are resorbed back into blood

• ionized drugs tend not to be reabsorbed (some exceptions & some drugs can use SLCs for resorption)

• passive resorption is influenced by drug lipophilicity & urine pH (affects ionization)

what is hepatic clearance? (CL_L)

• volume of plasma from which a drug is completely removed by the liver over a given time interval

• influenced by amount of drug excreted in bile & recycled into blood from intestine

enterohepatic recirculation

• drugs conjugated in liver

• excreted in bile

• microbes in intestine deconjugate drugs

• drugs reabsorbed into portal vein & returned to liver

cholangiocyte uptake of drugs

• lipophilic drugs: passively diffuse from blood into hepatocytes. not saturable

• ionized drugs: actively transported into cholangiocytes by SLCs. saturable

cholangiocyte efflux of drugs into bile

• lipophilic drugs: passively diffuse from cholangiocytes into bile

• ionized drugs: actively transported by ABC transporters

  • efflux favors large molecules, especially glucuronide conjugates

  • saturable

• metabolites can also move back into bloodstream

what does the milk-to-plasma drug-concentration ratio measure?

measures propensity for drug elimination in milk

pharmacogenetics

the study of genetic variation responsible for inter-individual variability in drug response and adverse drug reactions

genetic polymorphisms

• heritable DNA sequence variations that occur in ≥ 1% of the population

• different from mutations, which aren’t necessarily heritable & occur in <1% of the population

what are the effects of ABCB1-1Δ polymorphism?

• 4-base pair deletion mutation in dog p-glycoprotein

• deletion reduces p-glycoprotein activity

• increases sensitivity to many drugs, including ivermectins

  • dogs with 2 copies of the allele do not effectively efflux ivermectin from BBB, resulting in ivermectin neurotoxicity