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Arch Metab. Endocrinol 2017;61/4 (smoothmuscle cell),andskin(fibroblast vasculature cell), testes(Leydigcellandgerm and chondrocyte), placenta,, breast, muscle, (osteoblast cortex), the (hypothalamus, limbic system, and cerebral canbefoundatothersitessuchas but siteofaromatization, Adipose tissueistheprimary (2,3). ofcirculating the localaromatization mostly synthesizedlocallyinperipheraltissuesfrom is glandsandthetestes,whereas adrenal (NADPH)(1). reductase and nicotinamide-adenine dinucleotide phosphate CYP19 bytwoproteins: isacomplexformed and ,respectively. toestrone The and catalyzes the conversion of A INTRODUCTION ; ;shortstature;druginteraction;cytochromeP450 Keywords class ofaromataseinhibitors. recognizing andavoiding possibledruginteractionsandoffering asaferprescriptionprofileofthis effect onaromataseinhibition. Therefore, itisimportant thepharmacokineticsof tounderstand AIs, phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproatehas a synergistic CYP3A4 and by reducingtheclearance of AIs. Antiepileptic drugs(lamotrigine, phenobarbital, and of AIs. Druginteractionscanoccurwithazole antifungals, such asketoconazole,byinhibiting andglucoronidationareinvolvedother compounds.Hydroxilation, inthemetabolism N-dealkylation compounds thatcaninduceorsuppresscytochrome P450enzymes,interferingwithmetabolismof drugs, discussingpossibledruginteractionsbetween ANZ andLTZ with otherdrugs. AIs aretriazolic the hemegroupofcytochrome P450.Inthisreview, wedescribethepharmacokineticprofileofboth height. Anastrozole (ANZ)andletrozole (LTZ) to able tobindreversibly arenonsteroidalinhibitors (AI)inboyswithshortinhibitors staturehasshoweditscapabilitytoimprove thepredictedfinal ofbonematurationandclosureplate. one ofthemainregulators The useofaromatase androgens toestrogens. The aromatasegenemutationshighlightedtheactionofestrogenas Aromatase isacytochrome P450enzyme(CYP19A1 isoform)abletocatalyze theconversionof ABSTRACT Alessandra Linardi to know before prescribing? in boys stature: withshort what The useofaromatase inhibitors In males, androgens are produced bothbythe produced are In males,androgens identified as the CYP19A1 isoform, which identified astheCYP19A1isoform, P450enzyme, isacytochrome romatase 1 , Durval Damiani Arch EndocrinolMetab. 2017;61(3):391-7. 2 , Carlos A. Longui 3 potential reduction offinal height(10). potential reduction includes and bone age advancement with Theclinicalpresentation ofnewpromoters. recruitment (duplication, deletion, and inversion), with concomitant of recombination sub chromosomal iscausedby excesssyndrome other hand,aromatase (7-9).Onthe development andprimary gland also occur, mammary with inappropriate inatypicalgenitalia.Hypogonadismcan can result fertility. genitalia Ingirls,virilizationofthe external of glucose intolerance, hyperlipidemia, and reduction overweight, plate,osteoporosis, epiphyseal growth associatedwithdelayedfusionofthe tall stature (2,3,6). localeffects seemstohavepredominantly estrogen and hair follicle) (4,5). Peripherally synthesized Men with congenital aromatase deficiencyhave Men withcongenitalaromatase aspects andfinalapproval ofthe article conception,written participated equallyinthe Authorship: allauthorshave São Paulo, SP, Brasil Pediátrica, FCMSCSP, Unidade deEndocrinologia Disciplina deMedicinaMolecular, 3 (HCFMUSP), SãoPaulo, SP, Brasil Universidade deSãoPaulo da Faculdade deMedicinada Pediátrica, dasClínicas Hospital Unidade deEndocrinologia 2 (FCMSCSP), SãoPaulo, SP, Brasil CasadeSãoPauloda Santa Faculdade deCiênciasMédicas Unidade deFarmacologia, 1 DOI: 10.1590/2359-3997000000284 on Apr/6/2017Accepted Received onFev/13/2017 [email protected] 01221-020 –SãoPaulo, SP, Brasil Rua Dr. Jr., CesárioMota 112 CasadeSãoPauloda Santa Faculdade deCiênciasMédicas Unidade deEndocrinologiaPediátrica, Disciplina deMedicinaMolecular, deFisiologia, Departamento Longui Carlos A. Correspondence to: version senttobepublished. Departamento deFisiologia, Departamento dePediatria,Departamento deFisiologia, Departamento CYP19A1 review 391

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 392 daily orallyat doses of1mgand2.5mg, respectively. once administered are andletrozole Anastrozole PHARMACOKINETICS these drugs. ofabsorption, ,half-lifeandexcretion to interactionsrelated emergence ofpossibledrug tounderstand the in order included inthisreview ofbothinhibitorswas profile the pharmacokinetic Inaddition,abriefdescriptionof and otherdrugs. andletrozole interactions betweenanastrozole istodiscussthepossibledrug the aimofthisreview stature, inhibitorsinadolescentswithshort aromatase (18). withanastrozole treated group to the whencompared with letrozole in boystreated hasbeenreported andtestosterone of gonadotropins intheconcentrations increase agreater of letrozole, a singledailyadministration.Duetothehigherpotency type IIinhibitorshavealongerhalf-life,whichallowsfor (E1)andestradiol(E2)(17).Additionally, oftheestrogens the formation (> 95%) by suppressing blockingcompounds themosteffective are letrozole, and inhibitors,anastrozole aromatase nonsteroidal inhibitors.Thethird-generation reversible these are binding, P450.Despitethestrong of andbindtothehemegroup nonsteroidal type IIare inactivatingtheenzyme.Theinhibitorsof permanently totheactivesite,thereby enzyme. Theybindirreversibly the natural substrate of the aromatase androstenedione, andderivativesof steroidal type II.Type Iinhibitorsare (16). epiphyses atthefinalstageofpuberty ofthe maturation andclosure concentration determines duringpuberty, growth increases aswellathigh period,butevenatlowconcentration in theprepubertal ofgrowth intheregulation smallrelevance apparently has factor1 (IGF-1) (14,15).Estrogen like ogrowth (GH)andinsulin- ofbothgrowth secretion inthe concentration andconsequentreduction estrogen circulating level,associatedwithdecreased chondrocyte concentration at the epiphyseal of estrogen the reduction appeartobemediatedby upongrowth of thesedrugs (12,13). Theeffects stature forshort treatment receiving inboys skeletal maturationratehasbeenproposed theestrogen-dependent with thegoalofreducing inhibitors, bone maturation(11).Theuseofaromatase Use ofaromatase inhibitors Considering the increased prescription ofboth prescription Considering theincreased inhibitors can be divided into type I and Aromatase in playsakeyrole aswellitsreceptors, Estrogen,

on the monoamino oxigenase system. Lipophilic with themetabolismofothersubstancesdepending P450and,consequently,of cytochrome interfere Many azolecompoundscanbeinhibitorsorinducers ring. heterocyclic havea nitrogen-containing therefore (21). letrozole 60% for binding rate is around (20), while this isboundtoplasmaproteins 40% oftheanastrozole a 2.5-mgoraldose(19).Attherapeuticdoses,around after is4daysormore 48 hours,whilethatofletrozole afterasingle1-mgdoseis The half-lifeofanastrozole nonlinearkineticsofletrozole. is duetotheprobable 45-60days.Thisfact around while ittakesletrozole concentration, alsoknownassteadystate byfood(18). inhibitors isnotsignificantlyaffected 2 to4daysforthemboth.Oralabsorptionofboth around is reached Maximum estradiol suppression letrozole itself can exert significant inhibition over this itself can exert letrozole is metabolized by CYP2A6, Although letrozole for CYP3A4. for CYP2A6 and a low affinity high affinity hasa 2)(27).Thedrug (Figure the UGT2B7isoform by precisely , more conjugated by glucuronyl ittocarbinol(25,26). Carbinolisthen converting involvedinthemetabolismofletrozole, CYP2A6 are In vitro withtheuseoftherapeuticdoses(23). circulation inthesystemic notreached forthispurposeare required andtheconcentrations that describedforaromatase, this inhibitionoccurstoamuchlesserextentthan 2C9, and3A4inhumanmicrosomes isalsoabletoinhibit, anastrozole P450enzymes. Inaddition, involvement ofcytochrome undergo direct canalso pathway(24,25).Anastrozole a secondary UGT1A3 andUGT2B7canalsoactinthisphase,as transferase1A4(UGT1A4). is uridineglucuronyl 1). The main enzyme involvedin this step (Figure is extensivelyconjugatedbyglucuronidation and CYP2C8.Subsequently, hydroxyanastrozole mainly asCYP3A4and,lessimportantly, CYP3A5 N orcanalsoundergo metabolized intohydroxyanastrozole (22,23). phenylpyridines and phenylimidazoles, fit this profile such as nitrogen, compounds containingheterocyclic -dealkylation. The isoforms involved were identified identified involved were -dealkylation. The isoforms Anastrozole and letrozole are triazolicderivativesand are andletrozole Anastrozole the equilibrium plasma reaches Anastrozole Letrozole is also cleared viahepaticmetabolism. isalsocleared Letrozole P450(CYP), is viacytochrome Anastrozole, studieshavedemonstratedthatCYP3A4and in vitro conjugation (24) without prior conjugation(24)withoutprior Arch Metab. Endocrinol 2017;61/4 in vitro , after7days, . , CYP1A2, , CYP1A2, However, azole formulations and the IC50 of aromatase were were and theIC50ofaromatase azole formulations maximum plasmaconcentrations oforalandtopical (30).The with theactivityofaromatase can interfere Azole an INTERACTIONS DRUG doses(28). 467 nmol/Lafterrepeated concentration was107nmol/Lafterasingledoseand plasma themaximumletrozole Furthermore, asingleadministration. to thoseobtainedfrom parameters life whencomparingsuchpharmacokinetic half- inthedrug’s anda42%increase under thecurve inthearea a28%increase wasobserved there letrozole, dosesof cancerfollowingrepeated women withbreast showsnonlinear kinetics.In to explainwhyletrozole toCYP3A4(29).Thisphenomenonseems is diverted (28).Whenthisoccurs,themetabolicpathway isoform Arch Metab. Endocrinol 2017;61/4 isoforms. UGT2B7: uridineglucuronyltransferase(UGT)isoform. metabolic pathwaysareinbold. CYP2A6andCYP3A4: cytochromeP450 thus releasingthetriazolering. The mainisoformsinvolved in the carbinol isconjugatedtoaglucuronide. Letrozolecanundergodealkylation, to carbinolviacytochromeP450(CYPs)andthen, subsequently, the Figure 2. UGT2B7: uridineglucuronyltransferase(UGT)isoforms. CYP3A4, CYP3A5, and CYP2C8: isoforms. UGT1A4 and main isoformsinvolvedinanastrozolemetabolicpathwaysarebold. undergo dealkylation by CYP3A4, thereby releasing the triazole ring. The conjugation toglucuronide-OH-anastrozole. Inaddition, anastrozolecan hydroxyanastrozole viacytochromeP450(CYPs)andsubsequent directly toglucuronide- Figure 1. Glucuronide- UGT1A4 Letrozole metabolicpathways. Letrozoleisconvertedpreviously UGT2B7 Anastrozole metabolicpathways. Anastrozole canbecoupled tifungals, commonlyusedin clinicalpractice, Anastrozole Letrozole N -anastrozole N N -dealkylation -dealkylation N -anastrozole orpreviouslyconvertedto CYP3A4/5 CYP2A6 CYP2C8 CYP3A4 Triazole Triazole Glucuronide-OH-carbinol Glucuronide-OH-anastrozole Carbinol Hydroxyanastrozole UGT2B7 UGT1A4 UGT2B7 drugs can inhibit aromatase, includinglamotrigine, caninhibitaromatase, drugs on enzymeassaysshowedthatsomeantiepileptic with (31).Additionally, astudybased when used concurrently and anastrozole letrozole by ketoconazole is thepossibilityofinhibitionCYP3A4,especially there Furthermore, inhibitionofaromatase. greater absorptioncaninduce indrug means thatanincrease achieved byantifungalsintoconsideration,which this ratiotakesthemaximumplasmaconcentrations butonamuchsmallerscale.Importantly,aromatase, upon effect aninhibitory (vaginal). Theyalsoexerted itraconazole (oral),ketoconazole(oral)andmiconazole clotrimazole(topical), The otherazolesstudiedwere: initsabilitytoinhibitaromatase. letrozole approached thosethat (oral) andbifonazole(topical)were Among the azoles studied, miconazole performed. Co asasubstrate. afterusingtestosterone determined wine could be a natural inhibitor of aromatase, due wine could beanatural inhibitor of aromatase, Theauthorssuggest that red inestrogens. a decrease and inplasmatestosterone month inducedanincrease wineconsumptionduringone of ageshowedthatred 35years hand, astudyconductedwith womenaround following incubationwithethanol (36).Ontheother anincreas observed was cancercells,there MCF-7breast In cultured wine(35). rats, inducedbyboth13%alcoholandred activity inthehippocampusof aromatase increased (34). Previously, theauthorshadalsodescribedan intheadiposetissueofrats expression in aromatase cannabidiol (CBD),andcannabinol(CBN). Cannabis sativa withthemainconstituentsof asimilarresult observed (33). The authorsalso of the substrates ofaromatase one ofandrostenedione, and thesubsequentformation forthe17 responsible the activityofCYP17A1(P450c17),enzyme extract of thatthe itwasreported mouse testismicrosomes, aromatase. ontheinhibitionof hasasynergistic effect valproate Among these,theconcomitantuseofphenobarbitalor maybeanassociationbetween thedrugs. cases, there antiepileptics occurschronically, andthat,insome with to considerthat,inclinicalpractice,treatment itisimportant and ethosuximide(32).Therefore, oxycarbamazepine, tiagabine,phenobarbital,phenytoin, mparison with letrozole inhibitory potency wasthen inhibitory mparison withletrozole Alcohol consumption could induce an increase Alcohol consumptioncouldinduceanincrease totheuseof Regarding Cannabis sativa , such as tetrahydrocannabinol (THC), , such as tetrahydrocannabinol , which reduces theclearanceof whichreduces e in th α - of progesterone ofprogesterone -hydroxylation e expression of aromatase of aromatase e expression iscapableofinhibiting Cannabis Use ofaromatase inhibitors , whenstudying 393

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 394 stature. withashort children of not beenadequatelyinvestigated inthetreatment Theseaspects have ofthesedrugs. and excretion and neitherhastheinfluence onthetherapeuticeffect clarified, inhibitorshasnotbeenentirely of aromatase individual orracialvariability totheconjugationprofile theclinicalsignificanceof cancer (44).Nevertheless, inwomenwithbreast ofanastrozole therapeutic efficacy to byUGT1A4wascorrelated profile Glucuronidation (41-43). andletrozole the metabolismofanastrozole involved in respectively as UGT1A4 and UGT2B7 are such isoforms involvingglucuronyltransferase profile, duetopolymorphisms. altered may alsohave their activity Glucuronyltransferases needs additional studies. or anastrozole of letrozole variants involving CYP3A4 on plasmaconcentrations (4.2%) (40).However, theclinicalimpactofgenetic to white subjects among black(66.7%)ascompared inenzymeactivityandhasahigher prevalence increase clinical significance.Themostcommononeinducesan Polymorphisms involving CYP3A4 also have relevant thaninmen. CYP2A6 activityinwomenisgreater toCaucasians(1.2%)(39).Inaddition,the compared in theAsianpopulationislarger (10-20%)when ofslowmetabolizers populations. Thepercentage ethnic different tothegeneticvariationacross related One ofthepolymorphismsinvolvingCYP2A6is plasmaconcentrations (38). exhibit higher letrozole andslowmetabolizers toCYP2A6,intermediate respect because of polymorphisms. With or decreased increased mayhavetheiractivity CYP2A6 andCYP3Aisoforms The inhibitors, primarily identified for letrozole. ofaromatase inthemetabolic profile induce differences genetic polymorphisms may and letrozole, anastrozole activityorexpression. aromatase the otherhand,alcoholconsumptioncanincrease inhibitors.On also potentiatetheactionofaromatase and ofthesubstrateandrostenedione the formation addition, inhibitingtheenzymeactivity.inhibitors, further In antiepileptics maypotentiatetheactionofaromatase suchasazolesand demonstrate thatdrugs alcohol itself(37). ratherthan winethatpredominate, inred present flavones andisoflavones.Inthiscase,itisthechemicals of chemicalcompounds such asthe to thepresence Use ofaromatase inhibitors Significant individualvariationsintheconjugation of profile Relative to the pharmacokinetic together,Considered thesedataseemto Cannabis sativa and its correlates can reduce canreduce anditscorrelates a danger to life and require immediatemedical a dangertolifeandrequire interactionsas:major, drug whentheyrepresent classifies toemphasizethatMicromedex important interaction of moderate severity.only one drug It is ( an anticoagulant metabolized by both CYP3A4 ofwarfarin, orpharmacodynamics pharmacokinetics withthe in healthyadultvolunteersdidnotinterfere (23). Additionally, theadministrationofanastrozole for 30-fold lowerthanthoserequired are administration of therapeutic doses of anastrozole Plasma concentrations achieved bythe chronic shown to be inhibited by anastrozole. CYP3A were CYP3A4 (nifedipine), only CYP1A2, CYP2C9 and and (tolbutamide), CYP2D6(dextromethorphan), CYP1A2 (phenacetin),CYP2A6(coumarin),CYP2C9 andspecificsubstratesfor ofanastrozole presence with propranolol, during whichtheinhibitionof with propranolol, concentration; concomitant use in plasma letrozole association withtamoxifen, whichinducesareduction moderate severity interactions include: The three plasmaconcentration. in letrozole inan increase results ceritinib and idelalisib (antineoplastic agents), which agent), antimicrobial (macrolide by clarithromycin totheinhibitionofCYP3A severity interactionsrefer andvasodilator.antiaggregant major Theotherthree incilostazolplasmaconcentration,aplatelet increase may induce an inhibition of CYP2C19 by letrozole efficacy.5-fluouracil andlowerdrug Inaddition,the inlesser conversionoftegafurto mayresult letrozole agent tegafur, inwhich inhibitionofCYP2A6by severity interactions, we have the antineoplastic moderateinteractions.Relative to themajor three interactionsofmajor severityand show fivedrug 27% (46). plasmaconcentrationby approximately anastrozole cancer,women withbreast the tamoxifenreduced antagonist). In estrogenic tamoxifen (nonsteroidal totheconcomitantusewith refers with anastrozole interaction Themoderatedrug not recommended. is it impliesthattheconcomitantuseofdrugs andthecontraindicated, when change intreatment; a butdoes notrequire change intheclinicalpicture, therapy;minor,for achangeindrug whichsuggesta exacerbation ofthehealthconditionandneed inan moderate,whentheymayresult intervention; R -warfarin) andCYP2C9( -warfarin) The American database Micromedex reported reported The AmericandatabaseMicromedex incubatedinthe By usinghumanmicrosomes With regard to letrozole, Micromedex data Micromedex toletrozole, regard With S Arch Metab. Endocrinol 2017;61/4 -warfarin) (45). -warfarin) in vitro inhibition Arch Metab. Endocrinol 2017;61/4 besides and saquinavir), cimetidineandnicardipine, inhibitors(indinavir, protease amiodarone), ritonavir, (diltiazem, verapamil,and isoniazid), antiarrhythmics chloramphenicol,and erythromycin, (clarithromycin, itraconazole, fluconazole,voriconazole), antimicrobials venlafaxine), antifungals(ketoconazole, paroxetine, (fluoxetine,sertraline, to CYP3A4,antidepressants inducers orinhibitors(Table withregard 1).Therefore, foodandherbalessentialscanalsoactasenzyme as drugs, changes intheactivityofCYP2A6andCYP3A4,aswell tonotethatpolymorphismsleading it isimportant andletrozole, involved inthemetabolismofanastrozole P450. cytochrome of a significantchangeintheactivityofthisisoform doesnotappear toprovoke to CYP2C19,thedrug II)withrespect involving CYP2A6cannotbediscarded; interactions its plasmaconcentrationand,thus,drug cancausesignificantvariationsin kinetics ofthedrug namely:I)thenonlinear important, considerations are kidney (28). by the and subsequently excreted glucuronidation in vitro onCYP2B6andCYP2C19 hasbeenobserved effect the carbinolmetabolite,althoughamodestinhibitory individualvariability. andgreater drug to Inrelation forhigherplasmaconcentrations ofthe is responsible for CYP2A6. Thisphenomenon affinity to its greater isfivefold. CYP2A6, suchincrease inthe than thatobserved concentration that inhibits CYP2C19 is 40-fold greater The administration ofthedrug. plasma concentrations achieved during the chronic or carbinol(48). byincubationwithletrozole notaltered studied were onCYP2B6andCYP2C19.Otherisoforms effect hasalesssignificantinhibitory metabolite ofletrozole, inhibits CYP2A6andmodestlyCYP2C19.Carbinol,a by 38%(47). plasmaconcentration letrozole that tamoxifen reduces cancer showed postmenopausal women with breast Astudyof intheconcentrationofletrozole. increase inan potent inhibitorofCYP3A4,whichcanresult theassociationwithketoconazole,a of propranolol; theconcentration mayincrease CYP2C19 byletrozole Considering the cytochrome P450 isoforms P450isoforms Considering thecytochrome thefollowing ofletrozole, inrespect Therefore, mayalsoinhibititsownmetabolism due Letrozole aspectistoconsiderletrozole Another relevant significantly letrozole In humanmicrosomes, , carbinol is rapidly conjugated in vivo steadystate.For in vitro in vivo letrozole letrozole by and beverage ingestion, use of illicit drugs and plant andplant and beverageingestion,useofillicitdrugs interaction,food aspects,suchasdrug interfering should considertheconcomitanceofclinicallyrelevant of letrozole. profile CYP2A6 couldinfluencethepharmacokinetic inducersandinhibitorsof CYP2A6 (53,54).Therefore, in tobacco can also inhibit minor alkaloids present clonazepam mayinduceCYP2A6(50,52).Inaddition, hand, carbamazepine,phenobarbital,phenytoin,and Ontheother may inhibittheactivityofthisisoform. acid,selegilineandisoniazid suchasvalproic drugs (49-51).WhenconsideringCYP2A6, anastrozole themetabolismof all induceCYP3A4andincrease can and rifampicin,inadditiontoSt.John’swort phenobarbital, and phenytoin), dexamethasone, (carbamazepine, other hand,antiepilepticdrugs Onthe bythisisoform. metabolism ofanastrozole the mayallinhibitCYP3A4andreduce grapefruit, saturable, giventhatthedrugcaninhibit thisisoform. uridine glucuronyltransferase(UGT)isoforms. The metabolismofletrozolebyCYP2A6 is conjugation . CYP2A6 and CYP3A4: cytochrome P450 isoforms. UGT1A4 and UGT2B7: Phase I: metabolisminvolvingcytochromeP450enzymes (CYP). PhaseII: metabolisminvolving with inducersandinhibitorsofCYP Table 1. extracts. Individualmetabolicvariabilitydependenton Letrozole Anastrozole Drugs Therefore, when using aromatase inhibitors we inhibitorswe whenusingaromatase Therefore, Main metabolismenzymesandpotentialdruginteractionsassociated CYP3A4 CYP2A6 CYP3A4 Phase I Metabolism UGT2B7 UGT1A4 Phase II clonazepam phenytoin, and UGT2B7, John’s wort rifampicin, St. dexamethasone, phenytoin, phenobarbital, Carbamazepine, CYP3A4: Inducers Use ofaromatase inhibitors CYP tobacco alkaloids letrozole, and isoniazid, selegiline, Valproic acid, CYP2A6: grapefruit nicardipine, cimetidine, saquinavir, indinavir, amiodarone, verapamil, diltiazem, isoniazid, chloramphenicol, erythromycin, clarithromycin, voriconazole, fluconazole, itraconazole, ketoconazole, venlafaxine, paroxetine, sertraline, Fluoxetine, CYP3A4: Inhibitors 395

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