General ClinicalPharmacokineticsReview 2Universityof FloridaWorkingProfessionalDoctorof PharmacyProgramChristineCrain,Pharm.D.,BCPS
General Clinical Pharmacokinetics Review 2 University of Florida Working Professional Doctor of Pharmacy Program Christine Crain,Pharm.D., BCPS
ClinicalOuestion?A60yearold woman is taking quinidine fortreatment of atrialfibrillation. She has alsobeenprescribedfluconazolefortreatmentoa Candida UTland cisaprideto contro/sxOfGERD.Would you expect any of these drugs tointeractbasedonthehepaticenzymesbywhichtheyare metabolized?
Clinical Question? A 60 year old woman is taking quinidine for treatment of atrial fibrillation. She has also been prescribed fluconazole for treatment of a Candida UTI and cisapride to control sx of GERD. Would you expect any of these drugs to interact based on the hepatic enzymes by which they are metabolized?
Answer to Clinical OuestionHepaticEnzyme(s)AffectedQuinidineInhibits2D6Metabolizedby3A4FluconazolePotentialinhibitorof3A4CisaprideMetabolizedby3A4
Answer to Clinical Question Hepatic Enzyme(s) Affected Quinidine Inhibits 2D6 Metabolized by 3A4 Fluconazole Potential inhibitor of 3A4 Cisapride Metabolized by 3A4
DrugEliminationLiver-PrimarilyMetabolismKidney-PrimarilyExcretion
Drug Elimination Liver - Primarily Metabolism Kidney - Primarily Excretion
Hepatic ClearanceThe efficiency of the liver in removingdrugfromthebloodstreamis referredto as the extraction ratio (E)Withhighextractiondrugs,Eiscloserto 1Withlowextractiondrugs,Eiscloserto 0
Hepatic Clearance The efficiency of the liver in removing drug from the bloodstream is referred to as the extraction ratio (E). With high extraction drugs, E is closer to 1 With low extraction drugs, E is closer to 0
Hepatic ClearanceQHFCLiCLH =QH + FpCLiQH = Hepatic blood flowFp = Fraction of free drug in plasmaCLi= Intrinsic clearance
Hepatic Clearance CLH = QHFpCLi QH + FpCLi QH = Hepatic blood flow Fp = Fraction of free drug in plasma CLi = Intrinsic clearance
Hepatic ClearanceDrugs with a high intrinsic clearanceQHFCLiQHFpCLCLH =QH+ FpCLiFpCLiQHCLH =
Hepatic Clearance CLH = QHFpCLi QH + FpCLi Drugs with a high intrinsic clearance = QHFpCL i FpCLi CLH = QH
Hepatic ClearanceDrugs with a low intrinsic clearanceQHFCLiQHFpCLCLH =QH + FpCLiDCLH = FpCLi
Hepatic Clearance CLH = QHFpCLi QH + FpCLi = QHFpCL i QH CLH = FpCLi Drugs with a low intrinsic clearance
Intrinsic ClearanceLowHigh CLiCLiwarfarinpropranolollidocainephenytointheophyllinemorphinediazepamnitroglycerin
Intrinsic Clearance High CLi Low CLi propranolol warfarin lidocaine phenytoin morphine theophylline nitroglycerin diazepam
Clinical Ouestion?Smokingis knownto increasetheenzymesresponsiblefortheophyllinemetabolism.Would a patient with ahistoryofsmokinglikely reguireahigher,lower,oreguivalenttheophyllinetotaldailydosecomparedtoa nonsmoker?
Clinical Question? Smoking is known to increase the enzymes responsible for theophylline metabolism. Would a patient with a history of smoking likely require a higher, lower, or equivalent theophylline total daily dose compared to a nonsmoker?