Metabolism and Excretion Flashcards
Describe the general principles and consequences of drug metabolism.
- Drug-metabolizing enzymes have endogenous substrates and play role in normal metabolism.
- LIVER = primary organ of drug metabolism, but other tissues (e.g., lung [30%], kidney [8%], intestine [6%], placenta [5%], skin [1%], and bacteria in intestinal lumen) have enzymes capable of metabolizing drugs.
- OXIDATION = most frequent pathway, but others occur. Many transformations are catalyzed by membrane-bound enzymes of the smooth ER (CYP450 enzymes) and some by soluble enzymes in the cytosol.
- Lipid-soluble compounds are generally converted to more water-soluble (more polar) compounds that are then more readily excreted.
Generalities of Phase I / II transformation
Phase I: Usually inserts or unmasks a functional group on the drug –> more water-soluble –> undergo conjugation in a Phase II reaction.
Phase I reactions include: OXIDATION, REDUCTION, HYDROLYSIS
Phase II: Endogenous substrate combines with pre-existing or metabolically inserted functional group (via Phase I reaction) on the drug forming a highly polar (water-soluble) conjugate that is readily excreted via the urine.
Phase II reactions may also precede phase I reactions.
Generally, drug metabolism is a detoxifying process involving formation of readily excreted metabolites that are pharmacologically inactive (most common), but sometimes…
• Metabolism of active drug to MORE active compound (Codeine → Morphine, Hydrocodone → Hydromorphone)
• Metabolism of inactive compound (Prodrug) to active ingredient (designed) - e.g. Omeprazole → a Sulfenamide, Enalapril → Enalaprilat, Valacyclovir → Acyclovir
• Metabolism to toxic metabolite (relatively rare)
Acetaminophen → N-Acetyl-benzoquinoneimine (hepatotoxic)
Describe Phase I Oxidation
• Smooth ER in liver cels are richest source of enzyme
• CYP450 uses NADPH, the flavoprotein NADPH-cytochrome P450 reductase, and molecular O2.
CYP450 is dependent on NADPH & Fe
Substrate must be lipid soluble
Neonate level ~50-75%, but some drugs are metabolized faster
MANY isozymes
MANY genetic polymorphisms ranging from UM to PM (Amplichip can detect 2 major ones), this may explain Warfarin working only in some
CYP450 does pretty much everything except:
• Amine oxidases: Monoamine oxidase. Important enzyme in neurotransmitter metabolism. MAOI!!!
• Dehydrogenations: Alcohol/aldehyde dehydrogenase, hepatic soluble fraction
Describe Phase I Reduction
- Azo reduction: Involved in activation of certain sulfonamides.
- Nitro reduction: Several different enzymes (microsomal, soluble, bacteria). Can produce toxic intermediates.
- Carbonyl reduction
Describe Phase I Hydrolysis
- Esterases - reach adult values within first few months. Utilized in design of pro-drugs.
- Hydrolyze esters to corresponding alcohol and acid; extremely reactive enzymes
- Enzymes present in plasma, liver and other tissues
- Amidases
- Primarily in liver and in gut flora
- Hydrolyze amides to acids and amines
Describe Phase II metabolism
Conjugation Rxns (aka “synthetic” transformations) Drug or drug metabolite is coupled (conjugated) to endogenous biochemical unit (highly reactive) provided by a coenzyme (therefore limited supply and reaction is more easily saturable than phase I reactions). Operative enzymes known as transferases. Product often (but not always) highly water-soluble and readily excreted.
- Glucuronidation - on & off in intestine = enterohepatic recirculation
- N-Acetylation - lots of variability;
- Glutathione Conjugation - more important for detox (carcinogens, pollutants, toxic metabolites)
- Sulfate Conjugation - Adds SO4, but limited supply so easily saturated
Explain the therapeutic consequences of induction and inhibition of metabolism.
Induction
• Maximal effects seen in 7-10, need similar time to dissipate.
• Production of pharmacokinetic tolerance: induction by a drug of its own metabolism
• Induction by one agent may increase the clearance of other drugs –> reduced therapeutic effect or increased toxicity via a toxic metabolite.
• One drug may induce the metabolism of another to toxic metabolites; e.g., ethanol induces CYP2E1 that metabolizes acetaminophen to a hepatotoxic metabolite.
Inhibition
• Inhibition of metabolism can occur as soon as sufficient hepatic concentration is reached (generally within hours), although time to effect on steady state plasma concentration 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, and increased toxicity.
List the inducers
PP-CREST!! Phenobarb Phenotyoin Carbamazepine Rifampicin Ethanol St. John's Wort Tobacco
List the inhibitors
FECK HOG!! Fluoxetine Erythromycin/clarithromycin Cimetidine Ketoconazole/azoles HIV Protease inhibs Omeprazole Grapefruit juice
Describe the general characteristics of drug excretion by the kidney (filtration, secretion, reabsorption and the influence of pH and
protein-binding on these processes).
Glomerular Filtration (120mL/min): get drugs from blood --> urine. All FREE drugs will be filtered (not protein bound), must be smaller than albumin
ACTIVE Tubular Secretion (120-600mL/min): secrete acids or bases into the urine from the blood in proximal tubule.
Only acts on ionized compounds. On them, this can speed up renal excretion considerably. Protein binding is ok
Reabsorption: reuptake of drugs out of the urine, but drugs have to go through membranes to return to the bloodstream (thus have to be nonpolar, uncharged). Therefore, water-soluble, ionized, or large drugs (often conjugated or metabolized) CANNOT be reabsorbed.
Fastest renal excretion (filtration + secretion) rate is 600 mL/min (for ionized, large, water-soluble drugs)
Slowest (high reabsorption rate) is at the rate of urine excretion, about 1 mL/min (for nonpolar, small, lipid-soluble drugs).
Describe the therapeutic implications of enterohepatic recirculation of drugs.
• Many big drugs are excreted into bile –> reabsorbed from SI –> eliminated in the urine, rather than the feces
• Drug metabolites (as conjugates, inc MW) are also secreted into the bile –> hydrolyzed by bacterial enzymes back to the parent drug (more lipid-soluble) –> reabsorption from the gut (enterohepatic recycling).
EXTEND THE HALF-LIFE OF DRUGS
