Drug Metabolism and Excretion Flashcards
General principles and characteristics of drug metabolism
Drug-metabolizing enzymes have endogenous substrates and play a role in normal metabolism.
The liver is the primary organ of drug metabolisnm but other tissues (e.g. intestine, 6%, lung, 30%, kindney 8%, skin 1%, placent 5%, and intestinal bacteria) have enzymes capable of metabolizing drugs.
Oxidation is the most frequent pathway, but other types of transformations can occur. Many transformations are catalyzed by membrane-bound enzymes of the smooth ER (CYP450 enzymes), and some by soluble enzymes in the cytosol.
Lipid-solumbe compounds are generally concerted to more water-soluble (i.e. more polar) compounds that are then more readily excreted.
Describe the general characteristics of Phase I and Phase II reactions:
Phase I:
Reactions: oxidation, reduction, hydrolysis
Enzymes: CYP450, reductases, esterases-amidases
Genetic polymorphisms: significant
Induction-Inhibition–> DDIs: significant
Developmental patterns: variable
Age changes: 1/3 decrease
Saturability: minimal
Phase II: Reactions: Conjugation Enzyme: Transferases Genetic polymorphisms: Significant Ind-Inh--> DDIs : Possible-less than Phase I Developmental patterns: variable Age changes: minimal Saturability: Substantial
Explain the therapeutic consequences of induction and inhibition of metabolism.
Induction:
Drugs may stimulate CYP450 system, resulting in increased drug-metabolizing ability (this is referred to as induction). Induction is often caused by increased synthesis of the enzyme protein, may cause increase in liver weight, marked proliferation of SER, increases in NADPH and CYP450 (generally requires 48-72 hrs to see onset of effect.
Therapeutic consequences of induction:
(7-10 days for maximal effect)
Production of pharmacokinetic tolerance
Induction by one agent may increase clearance of other drugs
Reduced therapeutic effect if inactivation is accelerated.
Increased toxicity if activation reaction is accelerated.
Increased toxicity if toxic metabolite is produced.
Inhibition: Many compound inhibit drug metabolism, more so in phase I enzymes (especially CYP enzymes) than phase II.
Onset of inhibitory effect can occur within hours:
-Inhibits synthesis of enzyme.
-Inhibitor can be a substrate competing for the enzyme.
-Inhibitor can inhibit enzyme away from the active site.
-Inhibition can be due to a formed metabolite that either covalent binds to the enzyme and destroys it (suicide inhibition) or forms a tight complex with the enzyme, inhibiting its further activity.
Therapeutic consequences of inhibition:
Inhibition of metabolism can occur as soon as sufficient hepatic concentration is reached (generally within hours)
Time to effect on steady state plasma concentration is dependent on the inhibited drug’s half life.
Inhibition by one agent of the metabolism of another can result in decreased clearance of the inhibited drug—> higher circulating plasma levels–> increased toxicity.
If an activating metabolic reaction is inhibited—> reduction in therapeutic effect.
Clinically Relevant Inducers
Phenobarbitol Phenytonin Cabamazepine Rifampin Ethanol St. John's Wort Tobocco Smoke
Clinically Relevant Inhibitors
Cimetidine Erythromycin/Clarithromycin Ketoconazole/Azole antifungals Fluoxetine (and other SSRIs) Grapefruit juice HIV protease inhibitors Omeprazole
General characteristics of drug excretion by the kidney.
Kidney: most important organ for drug excretion, especially water-soluble and non-volatile compounds.
Glomerular filtration:
Drug clearance by filtration occurs at rate of 120 mL/min.
All drugs smaller than albumin (MW 69,000) will be filtered.
One free drug is filtered (not protein-bound).
Renal excretion is primarily affected by renal blood flow and renal function.
Dugs cleared by this route have a half-life of 1-4 hrs, but extensive protein binding can prolong halflife.
Active Tubular Secretion:
Drugs are transported directly from blood into urine. Cleared at a rate of 120-600 mL/min.
Occurs with drugs that are stronger acids and bases in the proximal tubule via secretory mechanisms that are saturable.
Plasma protein binding does not appreciable affect rate of secretion
Process is poorly developed in neonates
Tubular Reabsorption:
Due to tubular reabsorption, drugs that are lipid-soluble and uncharged would be cleared at rate of urin formations (1 mL/min)
-Passive diffusion: occurs with lipid soluble molecules in proximal and distal tubules. As water is reabsorbed, lumen to blood back-diffusion is favored as drug is concentrated in luminal fluid.
Diffusion of weak acids and bases is dependent upon urine pH (non-ionized form only will diffuse across membrane)
Can change urine pH with Ammonium Chloride/Ascorbic acid (to acidify) or Sodium hydrogen carbonate (to alkalinize)
-Active reabsorption is particularly important for endogenous compounds (glucose, amino acids). Most drugs act by reducing this active transport, rather than enhancing it.
Describe the therapeutic implications of enterohepatic recirculation of drugs.
Drugs/drug metabolites with MW >300 may be excreted via bile, stored in gallbladder, delivered to the intestines by the bile duct, and then reabsorbed into circulation, where it can returned to the liver.
- -> THis reduces the elimination of the drug and prolongs its half-life.
- -> Some drugs may have a reservoir of recirculating durg that can amount to about 20% of the total drug present. Antibiotics can reduce enterhepatic recycling and drecrease plasma drug levels, and is a potential mechanism for DDIs.
Describe the factors influencing drug passage from plasma to breast milk.
- Drugs with rapid clearance (>0.3 L/hr/kg) and no active metabolites are generally cleared too rapidly by the mother to affect the nursing infant.
- Milk is more acidic than plasma, therefore tendency to accumulate basic compounds (e.g. opiate analgesics) by ion-trapping
- Lipid soluble–> generally increased milk concentration
- High protein binding–> decreased milk concentration.
- Drugs that can affect milk synth., secretion and/or ejection through effects on prolactin or oxytocin release include: dopamine receptor agonists (decrease PRL release) and antagonists (increase PRL release) and ethanol (decrease oxytocin release)
