• elimination path- terminate activity
  • increases water solubility , leading to increase in excretion

• prodrug to active agent
• drug to inactive compound
• drug to toxic metabolite
• xenobiotic chemicals to mutagenic or carcinogenic compounds

• strategic location (pulls blood from GI)
• vast array of differnt enzymes

• phase I aka functionalization reactions
  • oxidations
  • hydrolyses
  • reductions
• phase II aka synthetic reactions
  • conjugations

Remember, that phase I and II DOES NOT MEAN THAT THIS IS THE SEQUENCE OF DRUG METABOLISM REACTIONS.

• any drugs or chemical can undergo more than one metabolism reaction
  • sometimes new drugs are found in drug metabolism pathways

microsomal

nonmicrosomal

• location- smooth ER
• named for spectral absorption when complexed with CO
• function
  • handles a wide variety of chemicals, drugs, endogenous metabolites (esp. steroid hromones)
  • usually leads to inactive metabolites
  • can lead to active or toxic metabolites or oxygen free radicals
• also called:
  • liver microsomal enzymes
  • mixed function oxidases

• N, S, O-dealkylations
• hydroxylation
• N-oxidation
• dehalogenation
• S-oxidation
• deamination
• desulfurylation

• 50 functional isozymes in humans
• 17 families + subfamilies and isozymes within subfamiles
• • based on AA similarities
  • CYP3A4 and CYP3A5- isoforms involved in metabolism of 50% of drugs
    • could potential lead to drug-drug interaction (one isoform compete with the other, usually leading to bad outcomes)

1. drug and cyc p450 form cyc p450-drug complex
2. cyc p450 (Fe³⁺)-drug complex and reduced flavoprotein to oxidized flavoprotein and cyc p450 (Fe²⁺)-drug complex via cyc p450 reductase (accepted reducing equivalent)
   1. oxidized flavoprotein and NADPH produce NADP and reduced flavoprotein
3. oxygen and reduced cyc p450 drug complex form cyc p450-drug oxygen complex
4. 2 H's and cyc p450-drug oxygen complex form water and cyc p450-drug OH complex (oxidized form)
5. cycp450 drug-OH complex form oxidized drug and cyc p450 (oxidized form)

• drug will be inactivated, so it will not make it into systemic circulation in as high a levels as if you gave orally (reduced amount of drug getting to systemic circulation than what you might expect)
• can also happen in GI tract (some p450 enzymes)

• the ability of a drug to increase its own metabolism upon repeated exposure
  • decrease in half life
• ex: increase in activity, plateu, than a gradual decrease as the days go on with treatment with phenobarbital

• drugs can induce metabolism of other drugs as well as their own by inducing the p450 system

• smoke
• polycyclic aromatic HC's
• charbroiled meats
• cruciform vegetables
• PCB's
• TCDD's

• increased rate of metabolism
• enhanced oral first pass metabolism and reduced bioavailability
• decreased drug plasma concentration
• reduced drug exposure

1. drug binds to nuclear receptor that mediates the process
   • similar to estrogen receptors
2. receptor sits on all places that contain response element in DNA
3. binding will drive transcription

• different receptors used for different p450 classes

• evolved to recognize a wide variety of subsrates
• mutations of variant AA's present in various species
  • leads to species specificity of ligand binding and activation

1. druyg bind, R dimerize, transcription occurs at response element
2. oxidation by cyp's, fmo's
3. conjugations by UGT's, GST's, ST's
4. transport proteins enhanced
5. efflux pumps enhanced

• derease metabolism rate
• decrease oral first pass metabolism with increase bioavailability (more in systemic circulation)
• increase drug plasma concentration

• MAO- metabolize epi, norepi
• ADH/aldehyde DH- metabolize shortchain alcohols
  • ethanol to acetaldehyde to acetate to FA's

• take place in cytoplasm and other organelles like mitochondria
  • also need source of reducing equivalents (NADPH/NADH; FADH)

• liver
• plasma

• apirin
• ACh
• local anesthetics
• antibiotics
• lipid lowering drugs
• meperidine
• cocaine

• examples
  • amidases
  • esterases
• location
  • cytoplasm
  • EC space
  • plasma

• location
  • GI tract
  • liver
• usually happens under low oxygen conditions (relatively rare)

• glucuronidation
• sulfation
• methylation
• acetylaTION
• glutathion conjugation

Require activate cofactors to synthesize drug conjugate

• cofactor- UDP glucoronic acid
• enzyme- UDP-glucuronyl transferase
• reaction
  • add UDP glucoronic acid to carboxylic acid group (benzoic acid) or hydroxyl group (phenol)

• enzyme- sulfotransferase
• cofactor- PAPS

• charged at physiological pH
• importance
  • kidney has specialized active transport system to pump conjugate into renal filtrate
  • charge allows it to be more water soluble

• ex of enzymes
  • PNMT (phenylethanolamine N methyl transferase)
  • COMT (catechol O methyl transferase)
• works on amines, phenols, sulfhydryls
• donor- SAM

• activated cofactor- acetyl CoA
• works on amines
  • sulfonamides
  • isoniazide
  • mescaline
• genetic control
  • fast and slow phenotypes
  • autosomal recessive

• substrate
  • chemically reactive compounds
  • metabolism of leukotriens
  • other endogenous substates
• function
  • detox
  • cell/DNA protection
• cofactor- glutathione

• delivery to liver by blood is rate limiting step of some drugs
• antihypertensives can reduce liver blood flow, leading to reduced metabolism

• hyperthyroidism- increase drug metabolism
• hypothyroidism- decrease drug metabolism

• way metabolites eliminated from body
• mainly renal and hepatic, but others are
  • lungs
  • breast milk
  • sweat
  • hair

• polar drugs
• hydrophilc metabolites

• glomerular filtration
  • passive
  • 40 A diameter
  • must be less than 28 kD
  • protein binding limits filtration of drug
• reabosrption
  • passive process dep on:
    • lipid solubility
    • ionization
  • ionized molecules stay in tubule
  • clinical ap: you can manipulate urine pH to alter reabsorption
• secretion
  • transporters in PCT
    • organic anions-PAH
    • organic cations-dopamine, histamine

• conjugated by either Gly or glucuronic acid
  • both process get saturated at certain points
  • to keep in urine, we want to send it into ionized form (A-) by making the solution more basic
    • free salicylate form INCREASES as pH more alkaline

• drug and metabolites excreted into bile than flows into hepatic duct, than gallbladder
• both acitve and passive process
• high molecular weight compounds tend to be eliminated in the bile
• examples
  • glucoronides
  • sulfates
  • glutathione metabolites
  • steroid hormones and conjugates

1. fate of drug in liver
   • can go into systemic circulation
   • can become drug-conjugate
2. if goes to drug-conjugate goes into intestinal tract as bile
3. at large intestines, drug-conjugate is broken apart to drug and conjugate by bacterial flora
4. the now free drug can be reabsorbed back into the liver where it could yet again:
   1. go into systemic circulation
   2. go into bile again

• acidification- NH₄Cl
• alkalinization- NaHCO₃