Pharmacology Conference

Abstract II

DRUG INTERACTIONS: ARE THEY AFFECTED BY SEX/GENDER? (continued)

Catherine A. White, Ph.D.

Many adverse drug-drug interactions are attributable to pharmacokinetic problems and can be understood in terms of alterations in absorption, distribution, metabolism or excretion. The pharmaco-kinetics/pharmacodynamics of drugs can also be affected by other factors such as foods, nutritional supplements, alcohol, smoking, toxins and hormones. The risk of clinical consequences from drug interactions is higher with some classes of drugs, particularly those with a narrow therapeutic window. Since sex/gender clearly influences the pharmacokinetics of some drugs, it should also be expected to play a significant role in the incidence and severity of drug interactions. A review of the literature has demonstrated sex differences in the interaction of drugs with other drugs/factors which affect active tubular secretion, intestinal and hepatic metabolism, toxicity and distribution of drugs in animals. However, these interactions have not been well documented in humans since very few studies have examined the effect of sex/gender. Until recently, very few women were included in drug interaction studies with the exception of oral contraceptives and hormone replacement therapy and in many studies where both men and women were included, the results were combined and no analysis for sex differences were done. The effect of sex/gender on drug interactions is an area in which a strong research effort is needed. This is of great importance in disease states, such as AIDS, in which patients are on multiple drug therapy, a known risk factor for adverse drug reactions/interactions. Adverse drug reactions in women appear to occur at a higher rate in both hospital and community settings, however, it is not known if sex/gender based drug interactions are responsible for the increased toxicity and adverse reactions associated with drug therapy in women. Additionally, studies need to be conducted in both sexes to determine the mechanism(s) responsible for these interactions. This presentation will focus on drug-drug interactions involving first pass effects and clearance, drug-food interactions involving grapefruit juice, and drug-ethanol interactions as well as provide an overview of what types of sex/gender drug interactions can be expected based on the known sex/gender differences in pharmacokinetics.

CHRONOPHARMACOKINETICS

Gaston Labrecque, Ph.D.

In the last 25 years, studies showed that time of day was an important variable influencing the kinetics of drugs. These observations lead to the development of a new discipline called chronopharmacokinetics which investigates: 1) the variations in drug plasma levels as a function of time of day and, 2) the mechanisms responsible for the time-dependent variations. The early studies indicated that the rate of absorption of aminophylline, ASA, indomethacin, ketoprofen or diazepam was larger when ingested orally between 6 AM and 2 PM. These time-dependent changes are probably due to circadian variations in the GI tract (i.e.: gastric emptying time, mucosal motility, etc). These data have some clinical implications because the lower PM absorption rate could lead to subtherapeutic plasma concentrations of drugs, as shown with some theophylline preparations. Most of these studies were done in male volunteers, although some female volunteers were included in the studies. There was no special effort to determine whether the chronopharmacokinetic data were similar in male and female volunteers. In a study on the effect of dosing-time and sex-related differences in the pharmacokinetics, cefodizime was injected IV to 8 male and 8 female volunteers at 4 different time points: 6 AM, noon, 6 PM, midnight and blood samples were collected over a 24 hours period. The data indicated that: 1) there was no sex-related nor dosing-time differences in half-life ; 2) plasma (AUC) and total cumulative excretion of cefodizime were larger in female than in male volunteers. Another study done in 8 male and 8 female volunteers showed that lorazepam was absorbed more rapidly after the morning than the evening administration, but there was no sex-related difference in the pharmacokinetics of this agent. There is no doubt that time-dependent variations can be detected in the pharmacokinetics of many drugs and these data may have important clinical implications. However, data are lacking at this time to support the hypothesis that time-dependent variations in the pharmacokinetics of drugs are identical in male and female. A strong research effort is needed in this area.
Pharmacogenetic Differences: Phase I Drug Metabolizing Enzymes

Gail D. Anderson, Ph.D.

The Cytochrome P450 (CYP) family of enzymes accounts for 95% of all Phase I metabolism. Six CYP enzymes are responsible for the metabolism of the majority of drugs: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. The activity of the enzymes is dependent on both genetic, physiological and environmental effects. Genetic polymorphism in the expression of CYP2C9, CYP2C19 and CYP2D6 has been identified. The polymorphisms are genetically inherited as an autosomal recessive trait, that is not X-linked. Poor metabolizers (PM) are homozygous for the mutant gene. Extensive metabolizers (EM) are heterozygous or homozygous for the wild type gene. Ultrametabolizers have multiple copies of the gene. There is a large interethnic variability in the incidence of PM and ultrametabolizers.

CYP2D6 was the first reported polymorphism. CYP2D6 is responsible for the metabolism of over 40 drugs including many antidepressants, antiarrhythmics, analgesics and beta-blockers. Caucasians have an estimated incidence of 5-10% while Asian, African Americans, Arabs, Indians and Egyptians have a much lower incidence of < 2%. The clinical effect of the polymorphism dependents on whether the parent or the metabolite is the active compound. For most CYP2D6 drugs, a PM will have significant elevated plasma concentrations and possible toxicity. In the case of drugs with active metabolites formed by CYP2D6 (for example codeine), a PM may have a lack of clinical effect. The few studies that have evaluated the influence of sex on the incidence of PMs have not demonstrated a difference. In addition, the relative activity of CYP2D6 appears to be independent of sex.

CYP2C19 is responsible for the metabolism of S-mephenytoin, methylphenobarbital, omeprazole, phenytoin, diazepam and its active metabolite desmethyldiazepam. The incidence of poor metabolizers is 15-25% in the Asian population compared to 2-5 % found in the Caucasian and African-American populations . Only a few studies have reported an analysis of the influence of sex on the incidence of the polymorphism. In the 6 studies that reported the data, the incidence was smaller in females in 2 studies, the same in 2 studies and higher in one; however none of the differences were statistically different. There is evidence of a sex difference in activity of CYP2C19, which is ethnic dependent. There was no sex related difference in Swiss, Jordian, Saudi Arabian and Filipino populations; however Chinese and African-American females demonstrated higher activity than found in the male subjects.

CYP2C9 is responsible for the metabolism of warfarin, phenytoin, lorsortan, tolbutamide and several non-steroidal antiinflammatory drugs (NSAIDS). The incidence of poor metabolizers has been recently identified in both Caucasians and Asians and is approximately 1/300 to 1/500. The overall incidence of PM may be too low to identify sex-related differences. Limited, but conflicting data suggest that there may be sex-related differences in the activity of CYP2C9.

CYP3A4 is the most abundant CYP in the human liver and is responsible for the metabolism of over 50% of all drugs. CYP3A4 activity does not demonstrate genetic polymorphism; however there is evidence of sex dependent differences in the metabolism of CYP3A4 drugs. Females demonstrate higher metabolism of many CYP3A4 drugs than found in males. There is evidence that there are also interethnic differences within females. Using 6-_-hydroxycortisol-cortisol ratio as a nonspecific marker of CYP3A4 activity, we found a 2-3-fold lower ratio in Chinese women compared to Caucasian women. This suggests that Chinese women may have less CYP3A4 activity than Caucasian women do.

In conclusion, there is only limited population data, however sex related differences in the incidences of poor metabolizer are unlikely. There are sex-related differences in the activity of the some of the CYP enzymes; which is ethnic dependent. Differences in ethnicity may mask potential sex related differences, if ethnicity is not taken into consideration in future studies.