The absorption and plasma levels of radioactivity were studied in female rats following a single transdermal application of ³H-TSH-01 (³H-labeled estradiol, E2).
1. The plasma levels of radioactivity reached the maximum at 4-8 hr after a single transdermal administration of ³H-E2 and then the radioactivity decreased with T_1/2(4-48 hr) of 12.7-17.7 hr. C_max and AUC increased in a dose-dependent manner within a dose range of 8-32 μg/body.
2. In plasma, the unchanged compound (E2), the main metabolite (estrone) and unknown metabolite were detected by HPLC analysis. The unchanged compound accounted for at least 35% of radioactivity at 24 hr after a single transdermal administration of ³H-E2.
3. The estradiol was mainly detected in the application site of skin after a single transdermal administration of ³H-E2 at 16 μg/body.

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The plasma level and excretion of radioactivity were studied following a single intravenous administration of [¹⁴C]M17055 to male and female rats, and a female dog.
1. After a single intravenous administration to male and female rats at a dose of 0.3 mg/kg, plasma levels of radioactivity declined triphasically reaching at 48 hr the levels lower than 1/1000 of those observed at one minute after administration. Calculated CLtot, T_1/2βand T_1/2γ did not differ between male and female rats. But T_1/2α of female rats showed lower value than that of male rats.
2. After a single intravenous administration to male rats at doses of 0.1, 1 and 3 mg/kg, plasma levels of radioactivity declined in similar manner with that at a dose of 0.3 mg/kg. Although calculated CLtot tends to decline at 1 and 3 mg/kg, the T_1/2γ showed similar value at the dose range of 0.1-3 mg/kg.
3. Plasma level of radioactivity in a female dog declined triphasically reaching at 48 hr the levels 100 fold lower than those observed at 5 minutes after a single intravenous administration at a dose of 1 mg/kg. There-after, the level of radioactivity declined more slowly when compared with rats.
4. Cumulative urinary and fecal excretions of radioactivity within 168 ho urs after a single intravenous administration to male and female rats accounted for 94.10 and 97.61% of the dose, respectively. Over 90% of the dose was excreted within 48 hours after administration. Urinary excretion rate was higher in female rats than that in male rats, especially within 6 hours after administration.
5. Cumulative urinary and fecal excretions after a single intravenous administration to a female dog accounted for over 90% after administration. Total excretion of radioactivity within 168 hours accounted for 97.33% of the administered dose.
6. Biliary excretion of radioactivity after a single intravenous administration to bile-duct cannulated male rats accounted for 64.12% of the dose. About 67% of the excreted radioactivity in bile was re-absorbed in male rats.
7. The renal clearance of radioactivity after administration in male and female rats decreased and showed same level when treated with probenecid, which suggested that the sex difference of the urinary excretion may be caused by the active secretary mechanism.

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Tissue distribution and the transfer of radioactivity into the fetus or milk were studied following a single intravenous administration of [¹⁴C]M17055 to rats at a dose of 0.3 mg/kg.
1. Tissue levels of radioactivity in male rats showed maximum level in most tissues at 5 minutes after administration. The concentrations in kidney and liver showed respectively 11.7 and 8.1 fold greater levels than that in plasma, while the levels in other tissues were lower than those in plasma. Then the levels of radioactivity in most tissues decreased to undetectable levels within 168 hours after administration.
2. Although higher kidney/plasma ratio of radioactivity was observed in female rats, the distribution of radioactivity in female rats showed similar pattern when compared with that in male rats.
3. After administration to pregnant rats on 12th and 19th day of gestation, a little radioactivity was transferred into the fetus and eliminated slowly in the rats on 19th day of gestation. Although temporary rising of radioactivity was observed in the intestine and its contents of the fetus, the radioactivity decreased to undetectable level in newborn rats at 168 hours after administration to the maternal rats. The distribution of radioactivity in pregnant rats showed similar pattern compared with that in non-pregnant female rats, which suggested that the influence of pregnancy on the distribution seems to have minimal effect in female rat.
4. The level of radioactivity in the milk reached a maximum level (63 ng eq./mL) at 2 hours and exceeded the plasma level within 2 ?? 12 hours after administration. Then the radioactivity decreased rapidly and reached lower level than that in plasma at 48 hours after administration.

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The plasma levels, tissue distribution and excretion of radioactivity were studied following repeated daily intravenous administration of [¹⁴C]M17055 to male rats at a dose of 0.3 mg/kg/day.
1. The plasma levels of radioactivity at 24 hours after each of 21 day-period of repeated administration to male rats were reached the steady state (6.90-8.87 ng eq./mL) by the 8th dosing. The calculated pharmacokinetic parameters were similar as those after the single administration.
2. Although the levels of radioactivity in all tissues at 24 hours after repeated administration to male rats rose according to the times of dosing, the rising rate was slow except for blood, lung, skin, digestive organs and their contents. At 1 hour after the 21st dosing, the radioactivity distributed highly to the liver and kidney as observed after the single administration. At 168 hours after the 21st dosing, the radioactivity tended to remain in highly perfused tissues, such as liver, kidney, spleen and lung. No tissue was identified in which the radioactivity retained for long period on the whole body autoradiograms.
3. Cumulative urinary and fecal excretions of radioactivity after 21 day repeated administration accounted for 58.17 and 37.35% of the total dose, respectively. The excretion rate in urine and feces well agreed to that after the single administration. The total excretion of radioactivity, including that present in the cage washing, accounted for 97.28% of the total dose.

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The functional genomics in drug discovery processes is usually recognized as the step to characterize the function of genes identified by sequencing human genome. The functional genomics, however, may have broader roles in the science at post-genome sequencing era. I will discuss my personal view on the potential roles of functional genomics in this chapter.

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The 43 member companies of the Japan Pharmaceutical Manufactures Association (JPMA) established the Pharma SNP Consortium (PSC), a non-profit organization, which will implement research programs over the three years between 2000-2003 with a total budget of 1 billion yen. The objectives of the PSC are to determine where SNPs influencing pharmacokinetics exist and how often they occur in Japanese population. The expression and functional analyses of variants generated under the influence of SNP will also be studied. The following are concrete research themes of the PSC: Standardization to collect samples from human donors; informed consent, protection of privacy (anonymity, information management system, etc.), ethics committee, and procedures (blood sampling, storage, etc.). And the analysis on gene polymorphisms (SNPs) related with pharmacokinetics; to identify SNPs of approximately 180 pharmacokinetics related genes, which are drug metabolizing enzymes and transporters, to analyze the allelic frequency of SNPs on a general Japanese population group composed of about 800 individuals, to generate a database for the analysis of SNPs allelic frequency, and to express variants in insect cells, analyze their function and examine the influence on the drug responses.
It is hoped that the PSC's plan will contribute to the development of the healthcare by constructing a common basis for the drug response analysis, create a more effective environment for the research on the human genome by the private sector in Japan by making standards to obtain blood samples, and furthermore facilitate discovery and development of safer and more effective medicines by cooperating with the Millennium Project.

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Human Genome Project (information and technology) provides insights so profound that it has the ability to change everything we know about medicine and how medicines are developed. Genetic factors contribute substantially to variable drug effects and constitute a critical element of a product's profile that must be considered in clinical use. Pharmacogenomics is a rapidly emerging field focused on understanding the genetic factors underlying drug action and applying this information to improve the clinical use and development of pharmaceutical products. In clinical practice, the understanding of how genetic variation leads to variable drug effects can be used to prescribe drugs selectively to individuals in regimens and doses that are most likely to be safe and effective (Personalized Medicine or “Tailor-made Medicine”). Also, pharmacogenomics will promote to develop novel pharmaceutical products targeted to the normal genetic variance of human populations. In drug development, knowledge of genetic variation that may affect drug action can be used to reduce the cost and complexity of clinical trials, increase the success rate of achieving regulatory approval, and achieve approvals for new classes of diagnostic and therapeutic products. Pharmacogenomics programs, thus, enhances the development, commercialization, and clinical use of conventional pharmaceutical products for common diseases, and eventually a powerful tool for Evidence-Based Medicine. Advanced genetic variance discovery technologies to optimize drug treatments and to develop safer and more effective pharmaceutical products, and clinical trial system to test for these variances are clearly required even in Japan, who unfortunately is still far behind in establishing this important discipline.

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In the last decade of the 20th century, the development of high throughput screening (HTS) and combinatorial chemistry technologies accelerated the drug discovery process. In the 21st century, emerging genomic technologies (i.e., bioinformatics, functional genomics, and pharmacogenomics) are shifting the paradigm of drug discovery and development. This review summaries recent advances in toxicogenomics and pharmacogenomics for drug discovery research. In particular, we describe genetic polymorphisms and single nucleotide polymorphisms (SNPs) of ATP-binding cassette (ABC) transporters which are critically involved in pharmacokinetics profiles of various drugs.

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In a broad sense, ethnic factors represent the fundamental problems in the acceptability of foreign clinical data. The mainstays of the harmonized final document about ethnic factors in the acceptability of foreign clinical data include a complete clinical data package and a bridging study (for efficacy and/or for safety). A clinical data package that meets all of the regional regulatory requirements is defined as a complete clinical data package for submission and potential approval, irrespective of its geographic origin. The accept-ability of the foreign clinical data component of the complete data package depends upon whether it can be extrapolated to the population of the new region. Ethnic differences can be classified into intrinsic and extrinsic factors. In many cases extrinsic factors, such as medical practice and custom, might more influence the availability of foreign clinical data than intrinsic factors. To overcome the difficulties inherent in ethnic differences, the bridging study concept was created. A bridging study is defined as a study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen that will allow an extrapolation of the foreign clinical data to the population of the new region. When a bridging study is designed, it is important to consider first which clinical studies in the foreign clinical data package are intended to be bridged or extrapolated. Then, the counterpart study should be selected from among available foreign clinical studies as the foundation of the bridge. The bridging study should be performed in the new region by the same or similar design to the design of the counterpart study in terms of subjects included, the duration of study, endpoint(s), evaluation method of clinical effects, etc. A bridging study could be relatively small, but the results of the study should be comparable with those of the counterpart of foreign clinical studies in all respects. The Clinical Trials Advice Division of the Organization for Pharmaceutical Safety and Research has been dealing with consultations about bridging studies since February 1998. Since then, numbers of consultations in relation to bridging studies have steadily been increasing. However, employing bridging study strategy is not always possible for various reasons. It should be noticed that the bridging study is not the only way to utilize efficiently foreign clinical data to promote the new drug approval, although the bridging study strategy may be the best desirable way, when possible, in order to utilize extensively foreign clinical data package.

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