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Conversion of the administered drug into another substance.
- Eliminated from the body faster than the parent drug:
- More polar
- Water soluble
- Where are these enzyme systems?
- Liver (primarily)
- GI tract, kidneys, lungs, brain, other
Factors that Affect Drug Metabolism.
- Genetics – “Pharmacogenomics/Pharmacogenetics”
- Plasma Protein Binding
- Disease States (kidney, liver function)
- Concomitant Drug Use
- Smoking and Alcohol (inducers of metabolism)
- Diet: Charbroiled foods, Grapefruit juice (Clin Pharm: blue “Find/List”) - inhibits
Phase I Metabolism
- Convert parent drug into more polar metabolite by:
Add or expose a functional group will alter biological properties.
Phase I Metabolism
Cytochrome P450 System
- Major enzyme system for Phase I reactions.
- Made primarily in live but also small intestine, kidneys, lungs, brain.
- 3 classes for drug metabolism: Cyp1, Cyp2, Cyp3
Drugs can be metabolized by more than one enzyme and enzymes can metabolize more than one drug.
Drugs can be:
Increase liver enzyme activity.
Increased activity = increased drug removal = decreased blood concentrations of substrate.
Dosage may need to be increased if the drug is an enzyme inducer.
Drugs can induce their own metabolism (autoinduction) which makes it difficult to determine dosage.
Drugs can inhibit metabolism of other drugs.
Usually competitive inhibition which slows metabolism.
Competitive binding = accumulation of drug = increased blood concentrations of substrate.
Dosage may need to be decreased.
Phase II Metabolism
Conjugation: addition of molecules naturally present in the body; glucoronidation (most common), methylation, acetylation.
- Facilitates elimination of drugs.
- Metabolite has improved water solubility (very polar).
- Increased molecular weight.
- Excreted in urine or bile
- Efflux transporter in GI tract, liver, kidneys.
- Transports certain lipophilic substances from blood into the gut, out of the brain, into urine, into bile, out of the gonads, out of other organs.
- First pass effect: removing it before it can be absorbed.
- Excreted almost exclusively by glomerular filtration (and some tubular secreation).
- Common measure of GFR
- Decreased GFR = increased serum Creatinine (Scr)
- Scr = clinical measurement of renal function.
- Scr can be used to calculate creatining clearance (CLcr)
CLcr = (140-age)(W) / Scr(72) = mL/min
- CLcr = (140-age)(W) / Scr(72) x 0.85 = mL/min
- W = kg
- Scr = mg/dL
- Normal clearance : 100-120 mL/min
- Impaired clearnace: <60 mL/min
- v.Impaired clearance: <30 mL/min
- likely dialysis depend: <15 mL/min
Factors that Influence Serum Creatinine and Estimation of CLcr
- Renal disease (most common)
- Liver disease = false low
- Hydration status = false high
- Malnutrition = false low
- Immobility = false low
IBW vs ABW
Men (kg) = 50 + [2.3(H-60)]
Women (kg) = 45.5 + [2.3(H-60)]
H = height in inches
If ABW < IBW = use actual
- If > 20% over IBW (overweight, obese)
- IBW + 30% of excess weight = IBW + 0.3 (ABW-IBW)
- The time required for drug concentration to reach steady state is determined by the drug's half-life:
- One half-life to reach 50% steady state
- Two half-lives to reach 75%
- Three half-lives to reach 87.5%
- Four half-lives to reach 93.75%
- Five half-lives to reach 96.875%
The attainment of steady state is assumed after 4-5 half-lives.
Increase in plasma concentration (and AUC) is linear (direct proportion) with drug dose. If drug dose increased 300mg to 600mg, serum concentration would also double.
Amount of drug eliminated in a specific time depends on the amount of dru in the body. The percent removed is constant.
- Elimination of drug does not depend on the concentration of the drug.
- The amount of drug eliminated is constant.
LD = (Vd)(Cp) / F
F = bioavailability