Yth. Peserta Diskusi ZOA-BIOTEK-2001,

Berikut ini kami sampaikan bagian pertama dari dua kali posting makalah 
Prof. Ishikawa tentang "Desain Molekul Obat berdasar Mekanisme Transport",


Kami mohon maaf, jika gambar tidak dapat tertampilkan dengan baik 
pada modus teks email. Bagi yang berminat, kami persilakan menengok 
website ZOA-BIOTEK di

http://sinergy-forum.net/zoa/paper/html/papertoshihisaishikawa.html

Selamat menikmati makalah Prof. Ishikawa.

Moderator

Dedy H.B. Wicaksono

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A New Challenge in the Post-Genome Era:
Transport Mechanism-Based Drug Molecular Design

Toshihisa Ishikawa
Department of Biomolecular Engineering
Graduate School of Bioecience and Biotechnology, Tokyo Institute 
of Technology

Waldemar Priebe
Department of Bioimmunotherapy, University of Texas M.D. Anderson 
Cancer Centery


Abstract

In the last decade of the 20th century, the development of high throughput 
screening (HTS) and high speed analoging (HSA) technologies helped 
accelerate the drug discovery process. In the 21st century, emerging 
genomic technologies (i.e., bioinformatics, functional genomics, 
and pharmacogenomics) may shift the paradigm for drug discovery and 
development. In the meantime, however, drug discovery and development 
will remain high-risk, high-stakes ventures with long and costly 
timelines. The attrition of drug candidates in preclinical and development 
stages is a major problem in drug design. At least thirty percent 
of the cases, this attrition is due to poor pharmacokinetics (e.g.
, limited absorption. Low plasma concentration levels, high rates 
of clearance). In the past, pharmaceutical companies have considered 
such early stage attrition an inevitable cost of doing business; 
however, as drug development costs have rocketed upward, pharmaceutical 
companies have begun to seriously reevaluate their current strategies 
of drug discovery and development. In that light, we propose that 
a transport mechanism-based design might help to create new, pharmacokinetically 
advantageous drugs, and as such it should be considered an important 
component of drug design strategy

Terjemahan Abstrak dalam Bhs. Indonesia
Tantangan Baru Era Pasca-Genome:
Desain Molekul Obat Berdasarkan Mekanisme Transport

Pada decade akhir abad 20, perkembangan high-throughput screening 
(HTS) dan high speed analoging (HAS) telah membantu mempercepat proses 
penemuan obat baru. Di abad 21, teknologi genomik yang baru bermunculan 
(seperti bioinformatika, genomic fungsional, dan farmakogenomik) 
mungkin akan menggeser paradigma pengembangan dan penemuan obat. 
Sekalipun demikian, untuk sementara ini, pengembangan dan penemuan 
obat masih merupakan usaha beresiko tinggi dengan modal besar dan 
membutuhkan waktu yang panjang. Tertolaknya kandidat-kandidat obat 
pada tahap preklinik dan tahap pengembangan masih menjadi masalah 
utama dalam deasin obat. Setidaknya dalam 30% kasus, tertolaknya 
kandidat obat ini akibat farmakokinetika yang jelek (seperti absorpsi 
yang terbatas, level konsentrasi plasma rendah, dan cepat terbilas 
habis). Di masa lalu, perusahaan farmasi menganggap bahwa kegagalan 
suatu kandidat obat di tahap-tahap awal.


Introductory Remarks

The attrition of drug candidates in preclinical and development stages 
is a major problem in drug design. At least thirty percent of the 
cases, this attrition is due to poor pharmacokinetics (e.g., limited 
absorption. low plasma concentration levels, high rates of clearance).
In the past, pharmaceutical companies have considered such early 
stage attrition an inevitable cost of doing business; however, as 
drug development costs have rocketed upward, pharmaceutical companies 
have begun to seriously re-evaluate their current strategies of drug 
discovery and development. In that light, we propose that a transport 
mechanism-based design might help to create new, pharmacokinetically 
advantageous drugs, and as such it should be considered an important 
component of drug design strategy.

Our strategy sprang from the realization that, in the near future,
the processes of drug discovery and development will be dramatically 
changed by the introduction of new research technologies such as 
bioinformatics, functional genomics, and pharmacogenomics and their 
use to identify both classical drug targets (e.g., enzymes, membrane-
bound receptors, and ion channels) and novel drug targets (e.g., 
cellular components of signal transduction, orphan nuclear receptors,
mRNA, and DNA). As a result organ-specific drug targeting and delivery 
will become increasingly important in ensuring the site selectivity 
and pharmacological activity and reducing the side effects of new 
molecular drug candidates aimed at those targets. 

Why are Drug Transporters so Important? 

Drug transporters and drug-metabolizing enzymes are important because 
they play pivotal roles in determining the pharmacokinetic profiles 
of drugs and, by extension. their overall pharmacological effects 
(i.e., drug absorption, drug distribution, drug metabolism and elimination,
drug concentration at the target site, and the number and morphology 
of target receptors) (Fig. 1), If a drug's concentration is too low 
at the target site (time course a), one can expect no pharmacological 
effect. If it is too high, one can expect side effects (time course 
c). Thus, in the best case, a drug's concentration at its target 
site (time course b) should be well controlled for sufficient periods 
by the action of factors controlling drug transport (influx and efflux) 
and drug metabolism. 



Figure 1.

Drug transporters are critically involved in the pharmacokinetics 
of drugs. For example, transporter proteins expressed in epithelial 
cells of the small intestine and in brain capillary endothelial cells,
greatly affect the oral bioavailability of drugs and their penetration 
into the central nervous system (CNS). From cancer chemotherapy studies,
it is known that overexpression of the transporter proteins P-glycoprotein 
(also called MDR1) and multidrug resistance-associated protein 1 
(MRP1 ) can render cancer cells resistant to anticancer drugs. Interestingly,
both P-glycoprotein and MRP1 belong to the ATP-binding cassette 
(ABC)-transporter family. This family of human ABC transporters is 
now known to contain more than 40 members, most of whose genes have 
been identified and sequenced. Evidence is also accumulating that 
human ABC proteins are involved in the transport of both drugs and 
endogenous substances and ions 1). 

(For detailed information, see URL http://www.gene.ucl.ac.uk/users/hester/abc.
html) 

P-glycoprotein, in particular, is gaining attention for its involvement 
in drug absorption by the small intestine and drug penetration into 
the brain; it is expressed in a variety of normal cells and organs,
and its modulation in these tissues can influence the activity and 
bioavailability of drugs. In the intestine, for instance, modulation 
of P-glycoprotein may control the degree of drug uptake after drug 
ingestion. At the blood-brain barrier, high P-glycoprotein levels 
can limit the uptake of desired drugs into the brain; conversely,
low P-glycoprotein activity can lead to abnormally increased accumulation 
and undesirable side effects.

Genetic Polymorphism of Drug Transporters 

The effects of drug transporters on the pharmacokinetic profile of 
a drug depend on their expression and functionality. Indeed, the 
expression of drug transporters can be modulatcd by endogenous and 
exogenous factors, including drugs, themselves. It is also now known 
that inherited differences among individuals may also affect drug 
efficacy and toxicity. Such inherited differences include genetic 
polymorphisms in drug targets and drug-metabolizing enzymes, as well 
as in drug transporters. Hitherto, pharmacogenetics, the field dealing 
with such inherited differences and their effect on pharmacokinetics,
has significantly contributed to our understanding of genetic causes 
underlying differences in drug metabolism (e.g., cytochrome P-450 
mediated drug metabolism). In fact, recent technological advances 
allowing massive molecular sequencing have in turn allowed a consortium 
of researchers to identify single nucleotide polymorphisms (SNPs) 
as one possible cause of variable drug response among individuals.
The SNP consortium plans to complete a high-density map of 300,000 
to 600,000 SNPs by mid 2001 and make it openly available to the public 
(http://snp/cshl/org) . In light of such advances, it is important 
to carefully examine the clinical significance, if any, of polymorphisms 
in drug transporter genes. 

Several preclinical reports have already noted naturally occurring 
polymorphisms in P-glycoprotein and their effects on drug absorption,
distribution and elimination; although the clinical relevance of 
these and other drug transporter polymorphisms has not yet been fully 
elucidated. Recently, however, Hoffmeyer et al. provided evidence 
of multiple polymorphisms in the MDR1 gene encoding human P-glycoprotein 
2). One of those mutations in particular, a C-to-T variant in the 
exon 26 of the MDR1 gene, was significantly correlated with P-glycoprotein 
expression and function; as a result, individuals homozygous for 
the polymorphism expressed significantly less duodenal P-glycoprotein 
and significantly more plasma digoxin. Hoffmeyer et al. also inferred 
that this polymorphism might affect the absorption and tissue concentrations 
of numerous other substrates of P-glycoprotein. From the discovery 
and characterization of drug transporter gene polymorphisms such 
as this one in the MDR1 gene may come a diagnostic test for discriminating 
between different MDR I alleles and better strategies for designing 
molecular anticancer drugs. 








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