antimicoticos azoles. farmacologia clinica
DESCRIPTION
FARMACOLOGIA CLINICA DE LOS ANTIFUNGICOS AZOLESTRANSCRIPT
• 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: [email protected]
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: [email protected]
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: [email protected]
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 ([email protected]),A.K. Ramasubramanian ([email protected])
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