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Toronto Notes 2019 Pharmacokinetics Pharmacokinetics
• studyof“whatthebodydoestoadrug”–i.e.thefateofadrugfollowingadministration
• definition:relationshipbetweendrugadministration,time-course/rateofabsorptionanddistribution,
concentration changes in the body compartments, and the drug’s removal from the body
Absorption
• definition:movementofthedrugfromthesiteofadministrationintoplasma
Mechanisms of Drug Absorption
• mostdrugsareabsorbedintothesystemiccirculationviapassivediffusion
• othermechanismsincludeactivetransport,facilitateddiffusion,andpinocytosis/phagocytosis
Factors Affecting the Rate and Extent of Drug Absorption
• Po/w
• localbloodflowatthesiteofadministration(e.g.sublingualvesselsfacilitaterapidabsorptionof
sublingually-administered medications)
• molecular size (e.g. drugs with smaller molecular weight are absorbed faster)
• pHanddrugionization
■ drugs are usually weak acids (e.g. ASA) or weak bases (e.g. ketoconazole) and thus exist in ionized and non-ionized forms
■ non-ionized forms cross cell membranes much faster than ionized (charged) forms
■ the ratio of ionized to non-ionized forms is determined by body compartment pH and drug pKa
(H-H equation)
• totalsurfaceareaforabsorption
■ small intestinal villi are the primary site of absorption for most oral drugs
Bioavailability (F)
• definition:proportionofdosethatreachessystemiccirculationinanunchangedstate • LowerFusuallyreflectslimiteddrugabsorptionorfirst-passeffect
• IVdosehas100%bioavailability(F=1)
First-Pass Effect
• definition:drugmetabolismbytheliverand/orthegutbeforeitreachessystemiccirculation,resulting in reduced F
• occurswithPOadministrationofadrug:GItract(absorption)→portalveintoliver(first-pass metabolism) → systemic circulation
• 50% of the PR administered drug absorbed in colon bypasses the portal system. CYP3A4 in the enterocytes reduce the bioavailability of some rectally administered medications
Efflux Pump
• Pgpisaproteinfoundinvariouspartsofthebodythatactsasamultidrugeffluxpumpinvolvedinthe transport of drugs out of cells
• forexample,Pgpopposesintestinalabsorption(e.g.dabigatranetexilate)andalsoenhancesrenal elimination of certain drugs (e.g. digoxin, etoposide, paclitaxel, tacrolimus, cyclosporine)
Clinical Pharmacology CP3
Po/w
• Ratio of a drug’s solubility in oil/lipid (e.g. cell membrane) as compared to water (e.g. extracellular fluid)
• A large Po/w (e.g. anesthetics) means that a drug is highly soluble in lipid and will cross cell membranes easily
Examples of Drugs with High First-Pass Effect
• Levodopa
• Morphine
• Propranolol
• Lidocaine
• Organic nitrates • Simvastatin
Examples of Drugs with Low First-Pass Effect
• Diazepam
• Digoxin
• Phenytoin
• Warfarin
• somedrugs(e.g.macrolideantibiotics)inhibitPgpfunction,leadingtoincreasedserumlevelsofdrugs transported by Pgp; Pgp inducers (e.g. rifampin, St. John’s wort) do the opposite
• sometumoursoverexpressPgpleadingtomultidrugresistancetochemotherapeuticagents
Distribution
• definition:movementofdrugsbetweendifferentbodycompartmentsandtothesiteofaction
• majorbodyfluidcompartmentsincludeplasma,interstitialfluid,intracellularfluid,transcellularfluid
(e.g. CSF, peritoneal, pleural)
• tissuecompartmentsincludefat,brain
Factors Affecting the Rate and Extent of Drug Distribution
• physiochemical properties of the drug (e.g. Po/w and pKa) • pHoffluid
• plasmaproteinbinding
• bindingwithincompartments(i.e.depots)
• regionalbloodflow
Total Body Water 60% of body weight
Extracellular Fluid 16-20%
Intracellular Fluid 40-44%
Intravascular Plasma 4%
Interstitial Fluid 12-15%
Figure 1. Distribution of total body water (TBW)