• SISTÉMICOS: Miconazol, Ketoconazol.

• TÓPICOS: Clotrimazol, bifonazol, oxiconazol, sertaconazol, flutrimazol, buconazol, econazol.

IMIDAZOLES

• Itraconazol, Fluconazol, Voriconazol, Posaconazol, Terconazol, Ravuconazol.

• Isavuconazol (BAL4815): profármaco en desarrollo fase III

TRIAZOLES

Anillo imidazólico libre unido mediante enlace C-N a otros anillos aromáticos.

En función del número de Nitrógenos que posee el anillo imidazólico se dividen en Imidazoles (2 nitrógenos) y Triazoles (3 nitrógenos).

Los azoles se unen al

grupo heme del citocromo y

bloquean la desmetilación

de lanosterol a ergosterol

Se acumulan compuestos

no desmetilados

• Los azoles se unen al citocromoP45014DM en dos lugares:

– Átomo de hierro del heme.

– Sitio de unión al sustrato.

• Mediante los átomos de Nitrógeno y losgrupos hidrófobos.

• Fundamental para la actividadantifúngica: unión del átomo N4 deforma covalente con el grupo heme.

Interfiere en la síntesis y la permeabilidad de la

membrana

• En general se absorben bien tras laadministración VO con una biodisponibilidad>90%.

• Itraconazol oscila alrededor 50%, las cápsulasrequieren medio ácido. La suspensiónpresenta mejor absorción y no es dependientedel ph.

Absorción

• La biodisponibilidad del Voriconazol aumentacon la administración de dosis múltiples reducción del metabolismo del fármacoautoinhibición que él mismo realiza sobrealgunas de las isoenzimas que participan en sumetabolismo.

Absorción

• Fluconazol es muy hidrosoluble y se absorbemy bien incluso en presencia de alimentos,antiácidos o anti H2.

• Itraconazol es insoluble en agua y muy solubleen lípidos se recomienda administración decápsulas con zumos de frutas y bebidas cola.

Absorción

• Fluconazol es muy hidrosoluble y se absorbe muybien incluso en presencia de alimentos, antiácidos oanti H2.

• Itraconazol es insoluble en agua y muy soluble enlípidos se recomienda administración de cápsulascon zumos de frutas y bebidas cola.

• Posaconazol se absorbe mejor con comidas ricas engrasa.

Absorción

• Los triazoles se distribuyen ampliamente porel organismo.

• Unión a proteínas baja, excepto Posaconazol eItraconazol.

• Fluconazol y Voriconazol alcanzanconcentraciones similares a las plasmáticas enLCR.

Distribución

• Itraconazol debido a su elevada unión aproteínas plasmáticas alcanza concentracionesmínimas en LCR y saliva, pero muy elevada enla mayoría de tejidos.

Distribución

• Presenta las mayores diferencias entre losdistintos triazoles.

• Fluconazol se elimina en mayor proporciónpor orina.

• Itraconazol y Voriconazol mayoritariamentepor metabolismo hepático oxidaciones ehidroxilaciones principalmente.

Metabolismo y Eliminación

• Itraconazol, Voriconazol, Posaconazol: Inhibidores con granactividad de CYP3A4.

• Voriconazol: además inhibe CYP2C9 y 2C19.

• Posaconazol: adicionalmente glucuronidación.

• Farmacocinética no lineal: aumento de las concentracionesconforme progresa el tratamiento gran influencia enefectos beneficiosos y adversos.

Metabolismo y Eliminación

Disfunción orgánica y dosis

Inhibición

Inhibición

Inducción

Patógeno fúngico

Agente antifúngico

Factores del huésped

OPTIMIZACIÓN DEL

TRATAMIENTO

ANTIFÚNGICO

Interacción entre:

Determinan

dosis eficaz

• T>MIC: Intervalos de dosis más cortos.

• Cmax/MIC: Dosis a intervalos más prolongados.

• AUC/MIC: Actividad varía de acuerdo a la dosis total, y no conel intervalo de dosificación.

• El parámetro que mejor describe la PK/PD de los azoles es larelación de 25:1 en modelos de infecciónpreclínica.

• 24 H ABC:MIC Exposición acumulada al fármaco por 24horas

Clinical pharmacodynamics of antifungals

David Andes, MDDepartment of Medicine, Section of Infectious Diseases, University of Wisconsin,

600 Highland Avenue, Room H4/572, Madison, WI 53792, USA

The field of antimicrobial pharmacodynamics examines the relationship

between drug pharmacokineticsand antimicrobial efficacy [1]. These studies

have been valuable for defining optimal antimicrobial dosing regimens and

the development of in vitro susceptibility breakpoints [2–5]. The concepts

encompassing this discipline have been defined most thoroughly with

antibacterial compounds [1]. With the advent of standardized in vitro

susceptibility testing with antifungal compounds, similar pharmacodynamic

investigations have been undertaken. Both in vitro and in vivo models have

demonstrated a correlation between drug dose, organism minimum

inhibitory concentration (MIC), and outcome [6–13]. These investigations

have been important for describing the relative potency of antifungal drugs

against a number of important pathogens. Recent in vivo pharmacodynamic

investigations have examined the relationship among drug dose, dosing

interval, MIC, and treatment outcome to define the specific pharmacody-

namic parameter and parameter magnitude predictive of antifungal

treatment efficacy.

Pharmacodynamic patterns of activity

A variety of in vitro and in vivo studies have examined the impact of

antibiotic drug concentration on antimicrobial killing over time or the time

course of activity [1]. Two factors define the time course of antimicrobial

activity. Thefirst is the impact of drug concentration on the extent and rate

antimicrobial activity. When organism reduction is enhanced by increasing

drug levels the pattern of activity is referred to as ‘‘concentration-

dependent.’’ Studies with drugs from the polyene and echinocandin class

have demonstrated concentration-dependent killing over a wide range of

Infect Dis Clin N Am 17 (2003) 635–649

E-mail address: dra@medicine.wisc.ed

0891-5520/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0891-5520(03)00063-1

Clinical pharmacodynamics of antifungals

David Andes, MDDepartment of Medicine, Section of Infectious Diseases, University of Wisconsin,

600 Highland Avenue, Room H4/572, Madison, WI 53792, USA

The field of antimicrobial pharmacodynamics examines the relationship

between drug pharmacokinetics and antimicrobial efficacy [1]. These studies

have been valuable for defining optimal antimicrobial dosing regimens and

the development of in vitro susceptibility breakpoints [2–5]. The concepts

encompassing this discipline have been defined most thoroughly with

antibacterial compounds [1]. With the advent of standardized in vitro

susceptibility testing with antifungal compounds, similar pharmacodynamic

investigations have been undertaken. Both in vitro and in vivo models have

demonstrated a correlation between drug dose, organism minimum

inhibitory concentration (MIC), and outcome [6–13]. These investigations

have been important for describing the relative potency of antifungal drugs

against a number of important pathogens. Recent in vivo pharmacodynamic

investigations have examined the relationship among drug dose, dosing

interval, MIC, and treatment outcome to define the specific pharmacody-

namic parameter and parameter magnitude predictive of antifungal

treatment efficacy.

Pharmacodynamic patterns of activity

A variety of in vitro and in vivo studies have examined the impact of

antibiotic drug concentration on antimicrobial killing over time or the time

course of activity [1]. Two factors define the time course of antimicrobial

activity. The first is the impact of drug concentration on the extent and rate

antimicrobial activity. When organism reduction is enhanced by increasing

drug levels the pattern of activity is referred to as ‘‘concentration-

dependent.’’ Studies with drugs from the polyene and echinocandin class

have demonstrated concentration-dependent killing over a wide range of

Infect Dis Clin N Am 17 (2003) 635–649

E-mail address: dra@medicine.wisc.ed

0891-5520/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0891-5520(03)00063-1

Cuando se considera la

unión a proteínas el target

farmacodinámico es

similar entre los fármacos

de las misma clase.

Pharmacokinetics

and Pharmacodynamics of Antifungals

David Andes, MDa,b,*aDepartment of Medicine, Infectious Diseases Section, University of Wisconsin,

600 Highland Avenue, H4/572, Madison, WI 53792, USAbDepartment of Medical M icrobiology and Immunology, University of Wisconsin,

600 Highland Avenue, H4/572, Madison, WI 53792, USA

Theroleof pharmacokineticsand pharmacodynamicshasgained increas-

ing recognition as critical for selection and dosing of antimicrobial thera-

peutics, including antifungal agents. The study of pharmacokinetics

involves understanding the interaction of a drug with the host, including

measurements of absorption, distribution, metabolism and elimination.

The study of antimicrobial pharmacodynamics provides insight into the

link between drug pharmacokinetics, in vitro susceptibility, and treatment

efficacy. Pharmacokinetic/pharmacodynamic (PK /PD) investigations have

been valuable for defining optimal antifungal dosing regimens and develop-

ing in vitro susceptibility breakpoints. Numerous in vitro, animal, and clin-

ical studies have been instrumental in characterizing the pharmacodynamic

activity of the triazoles, polyenes, flucytosine, and echinocandins against

Candida species. Several studies have begun to apply these principles to op-

timize therapy against filamentous fungi. The principles that havebeen used

to characterize pharmacodynamic characteristics of single antifungal drugs

are also beginning to be used to examine the more complex relationship en-

countered with combinations therapy.

Understanding of PK /PD principles can provide useful information for

the clinician, clinical trial development, and for development of microbiol-

ogy laboratory guidelines [1–3]. Antifungal pharmacodynamics allows the

clinician to choose the most potent drug and provides a guide to the

most efficaciousand safedoseand interval of administration for a particular

pathogen and infection site. For the pharmaceutical industry, preclinical

Funding: NIH/NIAID AI01767-01A1, AI067703-01, AI65728-01A1.

* Department of Medicine, Infectious Diseases Section, University of Wisconsin, 600

Highland Avenue, H4/572, Madison, WI 53792, USA.

E-mail address: dra@medicine.wisc.edu

0891-5520/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.idc.2006.06.007 id.theclinics.com

Infect Dis Clin N Am

20 (2006) 679–697

Louie et al demostraron

que el resultado del

tratamiento con

Fluconazol para Candida

albicans es dependiente

de la cantidad de

fármaco o exposición-

ABC, pero independiente

de la frecuencia de la

dosis

Pharmacodynamic parameter magnitude

Studies demonstrating the importance of a specific pharmacodynamic

parameter definewhether a drug class is likely to be most efficacious when

dosed frequently or infrequently. Additional studies have been undertaken

with organisms varying in susceptibility to thedrug to define theamount of

drug or pharmacodynamic parameter magnitudeneeded for efficacy. Studies

with numerous antibacterials have demonstrated that the magnitude of

a pharmacodynamic parameter associated with efficacy is similar for drugs

within thesameclass provided that freedrug levels areconsidered [1,21,22].

Furthermore, in extensive studies with antibacterials, this parameter

magnitude has been shown to be independent of the animal species, site of

infection, and most often theinfecting pathogen [1,2]. Most importantly, the

parameter magnitudenecessary for efficacy in animal modelshasbeen shown

tobepredictiveof efficacy inhuman infections[1–3].Thisconcordanceamong

speciesisnot surprising if oneconsiderstwo factors. First, thedrug target for

an antimicrobial is in theorganism and not in theanimal and doesnot vary

from speciesto species. Second, expressing drugdoseasapharmacodynamic

parameter magnitude corrects for differences in pharmacokinetics among

animal species [1–3].

Clinical impact of antimicrobial pharmacodynamics

The predictive value of animal model pharmacodynamics studies has

aided in several areas of clinical antimicrobial development. Analyses in

Fig. 2. Impact of fluconazole dose and dosing interval on outcome in a murine candidiasis

model. (From Andes D. In vivo pharmacodynamics of antifungal drugs in the treatment of

candidiasis. Antimicrob Agents Chemother 2003;47:1179–86; with permission).

638 D. Andes / Infect Dis Clin N Am 17 (2003) 635–649

Pharmacodynamic parameter magnitude

Studies demonstrating the importance of a specific pharmacodynamic

parameter definewhether a drug class is likely to be most efficacious when

dosed frequently or infrequently. Additional studies have been undertaken

with organisms varying in susceptibility to thedrug to define theamount of

drug or pharmacodynamic parameter magnitudeneeded for efficacy. Studies

with numerous antibacterials have demonstrated that the magnitude of

a pharmacodynamic parameter associated with efficacy is similar for drugs

within thesameclass provided that freedrug levels areconsidered [1,21,22].

Furthermore, in extensive studies with antibacterials, this parameter

magnitude has been shown to be independent of the animal species, site of

infection, and most often theinfecting pathogen [1,2]. Most importantly, the

parameter magnitudenecessary for efficacy in animal modelshasbeen shown

tobepredictiveof efficacy inhuman infections[1–3].Thisconcordanceamong

speciesisnot surprising if oneconsiderstwo factors. First, thedrug target for

an antimicrobial is in theorganism and not in theanimal and doesnot vary

from speciesto species. Second, expressing drugdoseasapharmacodynamic

parameter magnitude corrects for differences in pharmacokinetics among

animal species [1–3].

Clinical impact of antimicrobial pharmacodynamics

The predictive value of animal model pharmacodynamics studies has

aided in several areas of clinical antimicrobial development. Analyses in

Fig. 2. Impact of fluconazole dose and dosing interval on outcome in a murine candidiasis

model. (From Andes D. In vivo pharmacodynamics of antifungal drugs in the treatment of

candidiasis. Antimicrob Agents Chemother 2003;47:1179–86; with permission).

638 D. Andes / Infect Dis Clin N Am 17 (2003) 635–649

• Imidazoles más tóxicos.

• En general triazoles son bien tolerados, todos con perfil deefectos adversos similar.

• Náuseas

• Vómito

• Diarrea

Itraconazol: Excipiente hidroxipropil-Beta-

ciclodextrin utilizado para aumentar

solubilidad dextrinas son metabolizadas por

bacterias intestinales en glucosa sobrecarga

de carbohiratos favrece molestias intestinales.

• Hepatotoxicidad severa (rara).

• Aumento transitorio de

transaminasas y bilirrubina (1-

2%).

• Azoles inhiben las corrientes hERG de una formaconcentración-dependiente.

• hERG: Human-ether-a-go-go gen codifica lasubunidad formadora de poro de la corrienterectificadora de K cardiaco. Es determinanteprincipal de la repolarización ventricular y por lotanto del QT.

• Discromatopsia: discapacidad

para la visión de colores.

• Fotofobia.

Suelen iniciarse 30-60 minutos después de

una dosis oral, duran usualmente <1 h y

desaparecen de forma espontánea aunque

se mantenga el tratamiento.

No se sabe el mecanismo por el cual se

produce, es dependiente de la dosis.

• Rash: 5-15%.

• Fototoxicidad: no requiere exposición

previa, dependiente de la dosis del

fármaco y de la exposición a la luz UV.

• Aumenta el riesgo de Ca de piel

(escamocelular y melanoma).

•

• Itraconazol.

• Desequilibrio entre el nivel de

estrógenos libres y la actividad

androgénica.

• Dosis >600 mg/día.

Ginecomastia

Martin M V. The use of fluconazole and itraconazole in the treatment of Candida

albicans infections: A review. J Antimicrob Chemother 1999; 44: 429-37.

Incapacidad del fármaco para alcanzar la diana dentro de lacélula barreras de permeabilidad o sistemas de bombeo activodel compuesto hacia el exterior.

Cambios en la interacción fármaco-diana aumento del númerode copias de la diana o modificaciones debido a mutaciones.

Modificaciones en las enzimas de las vías metabólicas.

TECHNOLOGIES

DRUG DISCOVERY

TODAY

Overcoming ant ifungal resistanceAnand Srinivasan1,3, Jose L. Lopez-Ribot2,3,*, Anand K. Ramasubramanian1,3,*1Department of Biomedical Engineering, The University of Texas at San Antonio, San Antonio, TX 78249, United States2Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, United States3Department of South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, United States

Fungal infect ions have become one of the major causes

of morbidity and mortalit y in immunocompromised

pat ients. Despite increased awareness and improved

t reat ment st rategies, the frequent development of

resist ance to the ant ifungal drugs used in clinical set -

t ings cont r ibutes to the increasing toll of mycoses.

Although a natural phenomenon, ant ifungal drug resis-

tance can compr omise advances in the development of

effect ive diagnost ic techniques and novel ant ifungals. In

this review, we will discuss the advent of cellular -micro-

arrays, microfluidics, genom ics, proteomics and other

state-of-the ar t technologies in conquer ing ant ifungal

drug resist ance.

Sect ion editors:

Jurgen Moll – Boehringer-Ingelheim, Vienna, Austria.

Gemma Texido – Nerviano Medical Sciences S.r.l,

Nerviano, Italy

Int roduct ion

The origin of fungi can be dated back to more than 1500

mil l ion years [1]. Although highly diversified, only 0.5% of

fungal species are considered to be pathogenic to humans [2].

This population of pathogens includes the causative agents of

aspergil losis, candidiasis, coccidioidomycosis, cryptococcosis,

histoplasmosis, mycetomas, mucormycosis, and paracocci-

dioidomycosis, among others. Unti l the 19th century most

infectious diseases were attributed to bacterial, parasitic and

viral origins and perhaps any less-frequent cases of fungal

diseases that could have prevailed before the 1800s were not

recognized or documented [3]. After the discovery of antibio-

t ics, clinicians observed unusual microbial colonization and

disease symptoms during antibiot ic therapy. Slowly the pos-

sibi li ty of fungi to cause disease in humans became apparent.

It was reported that the severity of infections caused by

fungal organisms could range from moderate to fatal, also

depending on the site of infection and the immune status of

the patient. Moderate fungal infections including cutaneous

infections such as ring worm and athlete’s foot are common

in many individuals, including immunocompetent patients.

On the other hand, the mucosal and systemic infections are

often ‘opportunistic’; that tend to manifest when the immu-

nity is compromised, and often lead to l i fe-threatening infec-

t ions. Some of the most common causative agents of these

opportunistic mycoses are Candida albicans, Aspergillus fumi-

gatus and Cryptococcus neoformans. The common targets of

these pathogens have been immunocompromised indivi-

duals such as patients suffering from HIV-AIDS, diabetes,

cystic fibrosis and cancer [4,5].

Although targeting a small group of patients compared to

viral or bacterial counterparts, these infections are often asso-

ciated with high morbidity and mortal i ty rates [6]. On the basis

of a study conducted by National Institute of Health, in the

United States alone between 1980 and 1997, the mortal i ty rate

due to invasive mycoses has increased by 320% [7]. The study

also reveals that the incidence of fungal infections has paral-

leled with the increase in the number of immunosuppressed

individuals, organ transplants, autoimmune disorders and

carcinoma. The reason for high mortal ity and morbidity are

poor diagnosis, emergence of drug-resistance and lack of effec-

t ive antifungal therapy. Worsening disease severity and further

complicating treatment, some fungi can form ‘biofi lms’ that

Drug Discovery Today: Technologies Vol. 11, 2014

Editors-in-Chief

Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA

Henk Timmerman – Vrije Universiteit, The Netherlands

Drug resistance

*Corresponding author.: : J.L. Lopez-Ribot (jose.lopezribot@utsa.edu),A.K. Ramasubramanian (anand.ramasubramanian@utsa.edu)

1740-6749/$ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ddtec.2014.02.005 65

• Impacto de la genética sobre la respuesta y el desenlace clínico de un medicamento: 50’s.

• El interés se reavivó con la secuencia del genoma humano.

• Variación genética de los blancos farmacológicos: distintos desenlaces clínicos y

respuestas a los medicamentos.

FARMACOGENÉTICA

FARMACOGENÓMICA

• Farmacogenética: Disciplina biológica que estudia elefecto de la variabilidad genética de un individuo ensu respuesta a determinados fármacos.

• Farmacogenómica: estudia las bases moleculares ygenéticas de las enfermedades para desarrollarnuevas vías de tratamiento.

Educat ion: Teachingpharmacogenomics to prepare futurephysicians and researchers forpersonalized medicineDavid Gurw itz1, Abraham Weizman2 and Moshe Rehavi3

1Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel2Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel3Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel

The vision of personalized medicine, the pract ice of

medicine w here each pat ient receives the most appro-

priate medical t reatments and the most fitt ing dosage

and combinat ion of drugs based on his or her genet ic

make-up, seems to become more realist ic as our know l-

edge about the human genome rapidly expands. We

already know the reason for many types of adverse

drug react ions, w hich are often related to polymorphic

gene alleles of drug metabolizing enzymes. Moreover,

insight into reasons for poor drug efficacy, often related

to single nucleot ide polymorphisms or larger poly-

morphisms in genes encoding drug target proteins, has

been gained. There is a grow ing need to incorporate

this increasingly complex body of know ledge to the

standard curriculum of medical schools, so that the

forthcoming generat ion of clinicians and researchers

w ill be familiar w ith the latest developments in pharma-

cogenomics and medical bioinformat ics, and w ill be

capable of providing pat ients w ith the expected ben-

efits of personalized medicine.

As the Human Genome Project approaches its successful

complet ion, it becomes evident that modern medicine is set

to undergo a major transformat ion. The revolut ion of

personalized medicine, where each pat ient would receive

the most appropr iate pharmacotherapy, based on his or

her genet ic make-up, wil l affect almost every medical

discipl ine [1–16]. I t seems that the wealth of new

informat ion on the contr ibut ion of gene polymorphism to

human health, and to drug response var iabil i ty, wil l

change the pract ice of medicine. Although it would take

many years for the ant icipated genomic revolut ion to reach

cer tain clinical fields, each medical discipl ine wil l ult i-

mately be transformed by genomic informat ion technol-

ogies. Numerous complex diseases, such as asthma, type 2

diabetes, autoimmune disorders or mood disorders, exhibit

large var iabil i ty in pat ient responses to current pharma-

cotherapy. Indeed, the large magnitude of human genome

diversity, believed to harbor approximately ten mil l ion

single nucleot ide polymorphisms (SNPs), and its corre-

lat ions with drug response var iabil i ty, is beginning to

emerge [17–20].

An urgent need for incorporat ing pharmacogenomics

teaching into medical schools’ curriculums

Pharmacogenomics, the union of classical pharmacology

with modern genomics, is emerging as a novel medical

research field. Indeed, several medical schools in the

USA and Europe are in the process of incorporat ing

phar macogenomics teaching into their cur r iculums.

However, the number of schools offer ing such courses,

according to recent web searches, is rather scant . Unique

among leading medical schools is the Universit y of

Cal i fornia, San Francisco (UCSF) Medical School dedi-

cated graduate program in pharmacogenomics, int ro-

duced in 2001 (ht tp://www.ucsf.edu/dbps/pspg.html).

Hopeful ly, addit ional medical schools wi l l fol low this

example. Meanwhile, there is a growing need to

int roduce as many future cl inicians and biomedical

researchers to pharmacogenomics. Otherwise, the

ensuing shor tage of qualified researchers and phys-

icians could significant ly hamper the prol i ferat ion of

personal ized medicine.

As a first step, and in recognit ion of such emergent

needs, the graduate school of the Sackler Faculty of

Medicine at the Tel-Aviv University has introduced a new

course ent it led ‘I ntroduct ion to Pharmacogenomics:

Towards Personalized Medicine’ for the 2002–2003 aca-

demic year. The course is intended for graduate and

undergraduate students who have a basic background in

pharmacology and in human genet ics. The curr iculum for

this course is shown in Box 1, as a guide for graduate

schools interested in fol lowing this example.

At this stage, the course is not intended for our MD

students, whose extensive teaching curr iculum limits the

implementat ion of addit ional courses. Similar consider-

at ions prohibit more extensive pharmacogenomics edu-

cat ion at other medical schools. We expect that the

teaching of cl inical pharmacogenomics wil l eventually be

incorporated into standard MD programs, although thisCorresponding author : David Gurwitz (gurwitz@post .tau.ac.i l).

Opinion TRENDS in Pharmacological Sciences Vol.24 No.3 March 2003122

http://tips.trends.com 0165-6147/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0165-6147(03)00024-5

El descubrimiento y desarrollo

farmacológico ha sido

tradicionalmente un proceso lineal,

con poca retroalimentación de las

fases tardías para todo el proceso en

conjunto.

La adopción de una estrategia en medicina

personalizada para el descubrimiento y

desarrollo de nuevos fármacos necesita un

cambio del proceso lineal actual a uno

“heurístico” (utilización de reglas empíricas para

llegar a una solución)

Identificar el problema

Definir y presentar el problema

Explorar las estrategias viables

Avanzar en las estrategias

Lograr la solución

Volver para evaluar los

efectos de las actividades

“Diseño Racional de

Medicamentos”

MEDICINA PERSONALIZADA: VENTAJAS

INDUSTRIA FARMACÉUTICA

• Aumenta eficacia y reduce costos del descubrimiento de un fármaco.

• Reduce el tiempo necesario para un ensayo clínico.

• Surgimiento de nuevos target en genes para el descubrimiento de fármacos.

• Diferenciación de productos en el mercado.

PACIENTES Y CLÍNICOS

• Alta posibilidad de efecto deseado del medicamento.

• Baja probabilidad de efectos adversos.

• Estrategias de prevención.

• Terapias dirigidas.

• Disminución en costos. ?

• Mejor cuidado de la salud.

CITOCROMO P-450

• La mayoría de fármacos se metabolizan porenzimas contenidas en los microsomashepáticos: Citocromo P-450.

• Otros fármacos son metabolizados por laGlicoproteína P.

CITOCROMO P-450

• 1958: KlingenbergPigmento unido al monóxido decarbono.

• 1964: Omura y Sato hemoproteína, le dan el nombreCitocromo P450.

• Han sido identificadas en todos los linajes de vida orgánica.Se conocen más de 7700 secuencias.

• Nombre: P- pigmento. Proteínas celulares “cito”, coloreadas“cromo”, con un pigmento que absorbe la luz a unalongitud de onda de 450nm, donde el hierro del grupohemo es reducido y forma complejos con el monóxido decarbono.

CITOCROMO P-450

Gen que codifica la

enzima para

Citocromo P450

Familia Subfamilia Enzima

específica

dentro de la

subfamilia

• Nomenclatura:

CITOCROMO P-450

• En el humano los CYP son proteínas asociadas a las membranascitoplasmática, mitocondrial y del retículo endoplasmático actúanmetabolizando sustancias endógenas y exógenas presentes en lamayoría de tejidos del organismo.

• Superfamilia de hemoproteínas que catalizan diversas reacciones: la máscomún es una reacción monooxigenasa: inserción de un átomo deoxígeno molecular (O2) en un sustrato orgánico (RH) a la vez que otro elátomo de oxígeno es reducido a agua:

CITOCROMO P-450

• Las familias 1, 2 y 3 del CYP450 son las que catalizan la mayorparte de las recciones de biotransformación de fármacos.

• 70% de contenido hepático de CYP450 corresponde a estasfamilias.

• Las principales biotransformadoras son: CYP1A2, CYP2A6,CYP2B6, CYP2C9, CYP2C8, 2C19, 2D6, 2E1 Y CYP3A4, siendoCYP3A4 y CYP2D6 las dos más importantes.

POLIMORFISMO

• Existencia de múltiples alelos de un gen.

• Alelo: cada una de las formas alternativas quepueden tener un mismo gen que se diferencianen su secuencia y que se puede manifestar enmodificaciones concretas de la función del gen

• …FALTAN POLIMORFISMOS ESPECIFICOS DEAZOLES