Since its introduction II years ago,15, 77 the antipyrine test, devised to determine quantitatively the effect of individual environmental factors on hepatic drug-metabolizing capacity in normal subjects, has been widely used by clinical pharmacologists, as indicated by the large number of applications listed in Table I. Yet there have been several technical modifications, new extensions and unresolved problems, and an increasing number of apparently conflicting results. This warrants a fresh look at the antipyrine test and a critical reassessment of its applications and limitations.The conventional description of the antipyrine test almost always begins and ends with a recital of the special pharmacologic properties that uniquely qualify antipyrine for use as a test drug: rapid and complete absorption from the gastrointestinal tract, distribution in total body

Antipyrine was administered to identical or monozygotic twins and to fraternal or dizygotic twins. Individuals with identical genotypes (monozygotic twins) exhibited significantly less variability in antipyrine halflife than did genetically different individuals (dizygotic twins). Therefore variations in antipyrine metabolism appear to be determined genetically rather than environmentally. In the 36 twins tested, antipyrine half-lives varied between 5.1 and 16.7 hours. No significant correlation occurred between half-lives for phenylbutazone and antipyrine in the 28 twins who received both drugs.

A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies-have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that "personalized medicine is almost here" or that "individualized drug therapy will soon be a reality." As summarized herein, numerous reasons exist to show that an "unequivocal genotype" or even an "unequivocal phenotype" is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone.