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Toronto Notes 2019 Pharmacokinetics
Factors Affecting Drug Biotransformation
• geneticpolymorphismsofmetabolizingenzymes
■ for some enzymes, individual genotypes may alter the rate of drug metabolism (e.g. poor,
intermediate, extensive, or ultrarapid metabolizers)
■ may lead to toxicity or ineffectiveness of a drug at a normal dose
■ tamoxifen and codeine are prodrugs activated by CYP2D6 (nonfunctional alleles reduce
effectiveness, whereas overactive/duplicated alleles impart “ultrarapid metabolizer” phenotype)
■ warfarin is metabolized by CYP2C9 (nonfunctional alleles lead to greater effect and lower dose
requirements)
• enzyme inhibition may sometimes be due to other drugs
■ CYP inhibition leads to an increased concentration and bioavailability of the substrate drug (e.g. erythromycin [CYP3A4 inhibitor] can predispose patients to simvastatin toxicity [metabolized by CYP3A4])
■ grapefruit juice is a potent inhibitor of intestinal CYP3A4, resulting in numerous drug interactions (e.g. saquinavir AUC increased 3-fold, simvastatin 17-fold)
• enzymeinduction
■ certain medications enhance gene transcription leading to an increase in the activity of a
metabolizing enzyme
■ a drug may induce its own metabolism (e.g. carbamazepine) or that of other drugs (e.g.
phenobarbital can induce the metabolism of OCPs) by inducing the CYP system
• liverdysfunction(e.g.hepatitis,alcoholicliver,biliarycirrhosis,orhepatocellularcarcinoma)may
decrease drug metabolism but this may not be clinically significant due to the liver’s reserve capacity
• renal disease often results in decreased drug clearance
• extremes of age (neonates or elderly) have reduced biotransformation capacity, and doses should be
adjusted accordingly
• nutrition:insufficientproteinandfattyacidintakedecreasesCYPbiotransformation,andvitamin/
mineral deficiencies may also impact other metabolizing enzymes
• alcohol:whileacutealcoholingestioninhibitsCYP2E1,chronicconsumptioncaninduceCYP2E1
and increase risk of hepatocellular damage from acetaminophen by increasing the production of
acetaminophen’s toxic metabolite (NAPQI)
• smokingcaninduceCYP1A2,thusincreasingthemetabolismofsomedrugs(e.g.theophylline,
antipsychotics)
Elimination
• definition:removalofdrugfromthebody
Routes of Drug Elimination
• kidney(mainorganofelimination)
■ renal drug clearance = (glomerular filtration + tubular secretion) – (tubular reabsorption) ■ two mechanisms:
1. glomerular filtration
– a passive process, so that only the free drug fraction can be eliminated
– drug filtration rate depends on GFR, degree of protein binding of drug, and size of drug
2. tubular secretion
– an active process that is saturable allowing both protein-bound and free drug fractions to be excreted
– distinct transport mechanisms for weak acids (e.g. penicillin, salicylic acid, probenecid, chlorothiazide) and weak bases (e.g. quinine, quaternary ammonium compounds such as choline)
– drugs may competitively block mutual secretion if both use the same secretion system (e.g. probenecid can reduce the excretion of penicillin)
• tubularreabsorption:drugscanbepassivelyreabsorbedbacktothesystemiccirculation,countering elimination mechanisms
• renalfunction(assessedusingserumCrlevels)decreaseswithage(7.5mL/minperdecade)andis affected by many disease states such as diabetes
• stool:somedrugsandmetabolitesareactivelyexcretedinthebileordirectlyintotheGItract
■ enterohepatic reabsorption counteracts stool elimination, and can prolong the drug’s duration in the
body
■ some glucuronic acid conjugates that are excreted in bile may be hydrolyzed in the intestines by
bacteria back to their original form and can be systemically reabsorbed
• lungs:eliminationofanestheticgasesandvapoursbyexhalation
• saliva:salivaconcentrationsofsomedrugsparalleltheirplasmalevels(e.g.rifampin)
Clinical Pharmacology CP5
Cytochrome P450 System
The CYPs are a superfamily of heme proteins that are grouped into families and subfamilies according to their amino acid sequence. These proteins are responsible for the metabolism of drugs, chemicals, and other substances
Nomenclature: CYP3A4
“CYP” = cytochrome P450 protein 1st number = family
letter = subfamily
2nd number = isoform
The CYP1, CYP2, and CYP3 families metabolize most drugs in humans. The most important isoforms are CYP3A4 and CYP2D6; therefore, anticipate drug interactions if prescribing drugs using these enzymes
Examples of CYP Substrates, Inhibitors, and Inducers http://www.medicine.iupui.edu/CLINPHARM/ ddis/main-table
The Cockcroft-Gault Equation can Estimate CrCl in Adults 20 yr of Age and Older
• For males
CrCl (mL/min) =
[(140 – age in yr) x Weight (kg)] x 1.2 serum Cr (μmol/L)
• For females, multiply above equation x 0.85 • Useidealbodyweightinobesepatients
Limitations of Cockroft-Gault Equation
• In individuals with large muscle mass, the equation underestimates renal clearance
• In the elderly population, physiological loss of muscle mass may result in overestimation of renal clearance
Note, only applies when renal function is at steady state
Avoid toxicity from drug or metabolite accumulation by adjusting a drug’s dosage according to the elimination characteristics of the patient