Herb-drug interactionsOutlineEvidence for herb-drug interactionsDrug Interaction ResolutionPK vs PDPrevalence: unknown but under investigationSt. John’s wort (Hypericum perforatum)St John’s wortSt. John’s wort: PK interactionsSt. John’s wortClinical strategyWarfarin-herb interactionsSlide 13Warfarin and Chinese herbsWarfarin and “G” herbsWarfarin and lipid-based agentsCase ReportSlide 18Slide 19Slide 20Garlic (Allium sativum)Slide 22GinkgoGinkgo and psychotropicsKava (Piper methysticum)Licorice (Glycyrrhiza glabra)Licorice: positive interactionSurgery and Dental ProceduresSlide 29Slide 30Clinical copingChecking for herb-drug interactionsDental procedures: herb side effectsHerb-drug Herb-drug interactionsinteractionsCharlotte Gyllenhaal, Ph.D.Charlotte Gyllenhaal, Ph.D.1,31,3Gail Mahady, Ph.D.Gail Mahady, Ph.D.22Departments of Medicinal Chemistry and Departments of Medicinal Chemistry and Pharmacognosy,Pharmacognosy,11 Pharmacy Practice Pharmacy Practice22Block Center for Integrative Cancer TreatmentBlock Center for Integrative Cancer Treatment336-1870, [email protected], [email protected]►Evidence for herb-drug interactionsEvidence for herb-drug interactions►Pharmacokinetic (PK) versus pharmacodynamic Pharmacokinetic (PK) versus pharmacodynamic (PD) interactions(PD) interactions►St. John’s wortSt. John’s wort►WarfarinWarfarin►MiscellaneousMiscellaneous►Herb-drug interactions and surgical/dental Herb-drug interactions and surgical/dental proceduresprocedures►Use of computer databases for clinical questionsUse of computer databases for clinical questionsEvidence for herb-drug Evidence for herb-drug interactionsinteractions►Case reportsCase reportsUnderreported? 70% “don’t ask-don’t tell”Underreported? 70% “don’t ask-don’t tell”►Lab studiesLab studiesDefine mechanismsDefine mechanisms►Recent interest in CYP450 inductionRecent interest in CYP450 induction►Not necessarily borne out in trials Not necessarily borne out in trials ►Human studiesHuman studiesTrials using probe drugsTrials using probe drugsMay be too short or expensiveMay be too short or expensiveMay be done on healthy population (not always)May be done on healthy population (not always)Genetic polymorphismsGenetic polymorphismsMultiple drug/herb users, elderly patientsMultiple drug/herb users, elderly patientsDe Smet, Br J Clin Pharm 2006; 63:258-67Drug Interaction ResolutionDrug Interaction Resolution►Require dosage adjustmentsRequire dosage adjustments►Temporary or complete elimination of Temporary or complete elimination of one or the other agent to avoid serious one or the other agent to avoid serious consequencesconsequences►Close monitoring of the subjectClose monitoring of the subject►Total change of drug therapyTotal change of drug therapyPK vs PDPK vs PD►PK: absorption, distribution, metabolism, PK: absorption, distribution, metabolism, eliminationeliminationCYP450, PgPCYP450, PgPAbsorption from GI tract (laxatives)Absorption from GI tract (laxatives)►PD: pharmacological functionPD: pharmacological functionAnticoagulant drugs plus anticoagulant herbsAnticoagulant drugs plus anticoagulant herbsSedative herbs plus anesthesiaSedative herbs plus anesthesia►NegativeNegativeMostMost►Positive or synergisticPositive or synergisticPossible PD or PKPossible PD or PKDecrease side effectsDecrease side effectsPrevalence: unknown but under Prevalence: unknown but under investigationinvestigation►Canadian seniors with osteoarthritisCanadian seniors with osteoarthritisSurvey, n = 191. Average 2.8 prescriptions, 1.9 Survey, n = 191. Average 2.8 prescriptions, 1.9 self-care productsself-care products►Potential interactions detected using standard Potential interactions detected using standard databasesdatabases214 instances, 14% possible clinical significance214 instances, 14% possible clinical significance7 herbs/supplements, associated with 5 clinically 7 herbs/supplements, associated with 5 clinically insignificant interactionsinsignificant interactions1 recommendation to stop medications (dilatiazem 1 recommendation to stop medications (dilatiazem + atrorvastatin -> statin side effects intensified)+ atrorvastatin -> statin side effects intensified)Clinically significant interactions may be rare – but Clinically significant interactions may be rare – but thus easier to forget about and harder to monitor!thus easier to forget about and harder to monitor!Putnam, Can Fam Physician 2006; 52:340-45St. John’s wort (St. John’s wort (Hypericum Hypericum perforatumperforatum))►Mild-moderate depression -> long-term Mild-moderate depression -> long-term treatment; multiple clinical trials, fewer AEs treatment; multiple clinical trials, fewer AEs than conventional drugsthan conventional drugs►Case reports suggesting PK interactions Case reports suggesting PK interactions (most important of SWJ interactions)(most important of SWJ interactions)►Lab studies indicate PK interactions:Lab studies indicate PK interactions:►CYP450 3A4 mechanism CYP450 3A4 mechanism ►short-term inhibitionshort-term inhibition►Long-term induction; of most importance clinicallyLong-term induction; of most importance clinically►Reduces various drugs to subtherapeutic levelsReduces various drugs to subtherapeutic levels►Hyperforin, an active constituent, is a ligand for the Hyperforin, an active constituent, is a ligand for the xenobiotic pregnane X receptor -> CYP450 3A4 xenobiotic pregnane X receptor -> CYP450 3A4St John’s wortSt John’s wort►Other PK interactionsOther PK interactions►P-glycoprotein (PgP): involved in P-glycoprotein (PgP): involved in multidrug resistance, acts as a pump multidrug resistance, acts as a pump to remove drugs from cellsto remove drugs from cellsSJW induces this orphan nuclear receptorSJW induces this orphan nuclear receptorAlso regulates MDR-1 (multidrug Also regulates MDR-1 (multidrug resistance gene) and other drug resistance gene) and other drug transporterstransportersChavez, Life Sci 2006; 78:2146-57St. John’s wort: PK St. John’s wort: PK interactionsinteractions►Human trial with irinotecan (cancer)Human trial with irinotecan (cancer)Blood levels of active metabolite were reducedBlood levels of active metabolite were reduced►Other drugs affectedOther drugs affectedCyclosporin, tacrolimus, indinavir, nevirapine, imatinib,
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