Advances in pharmacogenetics and pharmacogenomics.

Large differences among normal human subjects in the efficacy and safety of many therapeutic agents are caused by genetically controlled polymorphisms of drug-metabolizing enzymes, drug transporters, and drug receptors. Development of pharmacogenomics as a new field has accelerated progress in pharmacogenetics by elucidating at the level of the human genome the inherited basis for those large interindividual variations. Examples discussed in this review illustrate how this approach can be used not only to guide new drug discovery but also to individualize therapy. Adverse drug reactions, often attributable to large differences among subjects in drug response, constitute a leading cause of death in the USA. Such high morbidity and mortality could be reduced by application of the principles of pharmacogenetics and pharmacogenomics, defined broadly as the study of genetically caused variability in drug response.

Implications for risk assessment of host factors causing large pharmacokinetic variations.

Normal human subjects vary widely in their capacity to eliminate many drugs and environmental chemicals. These variations range in magnitude from fourfold to fortyfold depending on the drug and the population studied. Pharmacogenetics deals with only one of many host factors responsible for these large pharmacokinetic differences. Age, sex, diet and exposure to other drugs and chemicals, including oral contraceptives, ethanol and cigarette smoking, can alter the genetically determined rate at which a particular subject eliminates drugs and environmental chemicals. These elimination rates, therefore, are dynamic and change even in the same subject with time and condition. Regulatory legislation has only recently begun to recognize this very broad spectrum of human susceptibility and the existence of multiple special subgroups of particularly sensitive subjects. In setting standards for environmental chemicals, EPA and NIOSH have attempted to protect the most sensitive humans and should be encouraged to continue this policy. For some drugs and environmental chemicals, the commonly used safety factor of 100 may be too low; for these chemicals large, interindividual pharmacokinetic variations produced by pharmacogenetic and other host factors may make a safety factor of 400 or 500 more adequate.

Noninvasive assessment in vivo of hepatic drug metabolism in health and disease.

Despite the availability of techniques and concepts for examining the physiologic processes of drug disposition and clearance by the liver in normal subjects and in patients with liver disease, important questions remain in this field. Major problems include high inducibility of hepatic drug-metabolizing enzymes, even in patients with liver disease (normal drug clearances can occur in liver disease patients who chronically ingest drugs that induce these enzymes); poor correlation between routine liver function tests, such as SGOT, SGPT, alkaline phosphatase, and bilirubin, and alterations of hepatic drug metabolism in hepatocellular disease; failure of all drugs to be similarly affected in liver disease, even for drugs with similar metabolic pathways. Nevertheless, certain test drugs, such as antipyrine and aminopyrine, whose clearances from plasma or saliva closely reflect their hepatic metabolism, may serve as probes to explore under normal and disease conditions how drugs are handled in the liver. Nevertheless, limitations in the use of antipyrine and aminopyrine metabolism as tests of hepatic function must be recognized: special conditions of patients may render results of these tests by themselves impossible to interpret. Utilizing additional drug substrates and measuring rates of formation of individual metabolites, as well as disappearance of parent drug, investigators may be able to research more effectively and in greater detail for interrelationships between liver disease and the processes of hepatic drug metabolism, hepatic blood flow, and even other, as yet unidentified, processes that influence liver and drugs interactions.

Assessment of methods to identify sources of interindividual pharmacokinetic variations.

The advantages and limitations of the 2 most commonly used methods to investigate interindividual pharmacokinetic variations are reviewed. The first method is based on pharmacokinetic comparisons made after repeated administration of a model drug such as antipyrine, before, during and after imposition of a carefully controlled environmental perturbation. A principal virtue of the test is the use of each subject as a control. Subjects are usually under near basal conditions with respect to factors capable of altering hepatic drug-metabolising capacity. Exceedingly sensitive, the test yields highly reproducible results. It has been useful as a research tool in identifying environmental factors for which dose-response curves can be generated and compared. However, the test requires careful selection and control of subjects, and it may be hazardous to extrapolate results to subjects under different, non-basal, environmental conditions. This method most frequently involves antipyrine as the test compound, but other drugs can and have been used. The results disclose that many host factors that influence antipyrine disposition also affect the disposition of other drugs metabolised by hepatic mixed-function oxidases. Recent refinement of the antipyrine test involves measurement of the rate constant for formation of each of the 3 main metabolites of antipyrine. Sensitivity and specificity of the test are increased through examination of the effect of each factor on a separate hepatic cytochrome P-450. Due to the labouriousness of this procedure and its requirement for several days of urine collection from each subject, metabolite analysis will probably remain an experimental method not applicable for screening populations. The second method involves a particular model based on multiple regression analysis. Relying on correlations with historical data of a qualitative nature, previous applications of this method have been retrospective, rather than prospective. Several such correlations could not be confirmed in normal subjects under the conditions of a controlled prospective experiment. Thus, prospective studies need to be performed to check results obtained with this method. The model used appears to enjoy certain advantages, including speed, simplicity, and ease of execution.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitative assessment of hepatic function by breath analysis after oral administration of (14C)aminopyrine.

The rate of hepatic metabolism of dimethylaminoantipyrine (aminopyrine), which occurs primarily through N-demethylation, was assessed by measurement of the specific activity of 14CO2 excreted in breath samples obtained 2 hours after oral administration of a trace dose of [14C]aminopyrine. The percentage of administered 14C excreted in 14CO2 in 2 hours was 7.0 +/- 1.3 (SD)% in control patients, and significantly less (P less than 0.01) in patients with portal cirrhosis (2.6 +/- 1.2%), fatty liver (4.7 +/- 1.1%), hepatitis (2.6 +/- 1.4%), and hepatic malignancy (3.5 +/- 1.8%). In 16 of 24 subjects with cholestasis not caused by malignant disease the mean 14CO2 excretion was normal. The 14CO2 excretion in patients with portal cirrhosis correlated highly with aminopyrine metabolic clearance rate (r equals 0.92), serum albumin (r equals 0.75), and retention of bromsulphalein (r equals 0.73). Abnormal 14CO2 excretion returned to normal in patients with hepatitis, when the hepatitis resolved. The data suggest that the aminopyrine breath test is a safe, simple, qualitative and quantitative liver function test.