Gregg M. Stave

Effect of age and gender on the activity of human hepatic CYP3A.

Many pharmacokinetic investigations in the elderly population reveal decreased clearance of lipophilic drugs metabolized by the cytochrome P450 enzymes; however, few studies have evaluated aging-dependent or gender-related changes in specific cytochrome P450 enzymes. The clearance of quinidine, midazolam, triazolam, erythromycin, and lidocaine declines with age; these drugs are metabolized by the isoform, CYP3A. To determine whether these metabolic effects are due to changes in CYP3A, the effects of age and gender on CYP3A activity were examined. The activity of the human hepatic cytochrome P450, CYP3A, was quantified in vitro as erythromycin N-demethylation in microsomes prepared from forty-three resected human liver specimens obtained from patients, age 27 to 83, with normal liver function. Erythromycin N-demethylation varied 5-fold in human liver microsomes. CYP3A activity was 24% higher in females than males (P = 0.027). CYP3A activity did not correlate with age, smoking status, ethanol consumption or percent ideal body weight. Large interindividual differences and a small female-specific increase in CYP3A activity were obtained. However, CYP3A activity was unaffected by age over the range of 27-83 years, suggesting that the aging-related alteration in the clearance of CYP3A substrates is secondary to changes in liver blood flow, size, or drug binding and distribution with aging.

Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol

The N‐demethylation of erythromycin and 6β‐hydroxylation of Cortisol are both functions of the glucocorticoid‐inducible CYP3A in human liver microsomes. To determine whether 6β‐hydroxylation and erythromycin N‐demethylation are catalyzed by similar or distinct CYP3A isoforms, erythromycin N‐demethylase activity, as reflected by the recently described 14[C]‐erythromycin breath test, was compared with urinary 6β‐hydroxycortisol/cortisol ratios, a measure of Cortisol 6β‐hydroxylase activity, in nine patients. Erythromycin N‐demethylation varied fourfold and 6β‐hydroxycortisol/cortisol ratios varied sevenfold among the subjects; no correlation was found between these activities (r2 = 0.065). New noninvasive tests of CYP3A strongly suggest Cortisol 6β‐hydroxylation and erythromycin N‐demethylation are performed by distinct CYP3A isoforms.

Effect of Smoking Status on Productivity Loss

Objective: The objective of this study was to describe health-related productivity losses in nonsmokers, former smokers, and current smokers using a large, cross-sectional database of U.S. employees. Methods: Volunteers completed the Wellness Inventory, an instrument measuring productivity losses related to 11 health conditions affecting employee health. Results are aggregated, dollarized, and reported by smoking group. Results: Current smokers missed more days of work and experienced more unproductive time at work compared with former smokers and nonsmokers. The average annual cost for lost productivity for nonsmokers was

Hepatic cytochrome P-4503A (CYP3A) activity in the elderly

2623/year compared with

Prevention of laboratory animal allergy

3246/year for former smokers and

Zygomycosis of the basal ganglia in intravenous drug users

4430/year for current smokers. More than half the costs were due to unproductive time at work. Conclusion: Current smokers incurred the highest productivity losses, which translated into higher costs to employers for current smokers. Costs were lower for former smokers and nonsmokers.

Primary and secondary allergies to laboratory animals

Elderly patients exhibit decreased clearance of multiple drugs biotransformed by the hepatic cytochromes P-450. The cytochromes P-450 are a superfamily of enzymes, which comprise a central component of phase I drug metabolism. Distinct isoforms metabolize specific drugs. In human liver microsomes, the glucocorticoid-inducible cytochrome P-450IIIA, CYP3A, catalyzes the N-demethylation of erythromycin. To examine the activity of hepatic CYP3A in elderly males and females, erythromycin N-demethylation was examined, as reflected by the recently described [14C]erythromycin breath test in 24 healthy volunteers, age 70-88. The [14C]erythromycin breath test was measured in normal elderly males and females to: (a) determine persistence of the gender-related dimorphism (evident in younger subjects) of CYP3A activity in the elderly population, (b) examine the effect of % ideal body weight, age, diet, and medication use on the activity of human hepatic CYP3A, and (c) compare breath test results obtained in normal geriatric volunteers with published results obtained in younger subjects, to determine aging-related alterations in CYP3A enzyme activity. Erythromycin N-demethylation varied fivefold among these patients. Similar to earlier studies examining erythromycin N-demethylation in younger subjects, CYP3A activity was found to vary with gender in the geriatric cohort. [14C]Erythromycin N-demethylation at 60 min was 3.14% +/- 0.75 (n = 13) in females and 2.15% +/- 0.77 (n = 11) in males (P = 0.005). In evaluating the role of % ideal body weight and % dietary fat using multivariable linear regression analyses, [14C]erythromycin N-demethylation, was found to decline significantly as % ideal body weight increased (P = 0.001). This was not confounded by gender. [14C]Erythromycin N-demethylation was not related to dietary fat intake (P less than 0.13). [14C]Erythromycin N-demethylation in the elderly volunteers was similar to values reported for subjects aged 20-60. Performance of a new non-invasive test of the human hepatic glucocorticoid-inducible CYP3A in a geriatric cohort suggests that: (a) the gender-related heterogeneity in function of the glucocorticoid inducible human CYP3A persists during normal aging, (b) that the activity of CYP3A may decrease in obesity, and (c) that the activity of CYP3A is stable throughout normal ageing.

Evaluation of a Workplace Hemochromatosis Screening Program

Laboratory animal allergy (LAA) is a significant occupational hazard for workers in a number of research settings, including the pharmaceutical industry. Prevention of allergy and asthma is important because the illness can affect health and career. In a major pharmaceutical company, in an effort to prevent LAA, a comprehensive program to reduce exposure to environmental allergens was developed. The program included education, engineering controls, administrative controls, use of personal protective equipment, and medical surveillance. A prospective survey of five years of data was completed to determine the effect of the program on the prevalence and incidence of LAA. After instituting this program, we found that the prevalence of LAA ranged from 12%-22% and that the incidence was reduced to zero during the last two years of observation. We concluded that LAA is preventable through the implementation of a comprehensive effort to reduce exposure to allergens.

Prevention of laboratory animal allergy in the United States: a national survey.

Zygomycosis of the basal ganglia should be recognized as a syndrome in intravenous drug users associated with a culture-negative cellular CSF, fever, lethargy, and lesions apparent on contrast-enhanced CT scans of the head. The infection is most likely the result of intravenous inoculation of fungal spores. This entity is different from the rhinocerebral zygomycosis seen with diabetes mellitus and other diseases. In the rhinocerebral form, there are external signs of the disease with involvement of the orbit, paranasal sinuses, and palate. In these drug users, infection was directed to areas deep within the brain.

Evidence-based benefit design: toward a sustainable health care future for employers.

Although laboratory animal allergy (LAA) is a significant occupational hazard among workers exposed to laboratory animals, few studies have evaluated long-term risks to workers who remain in the workplace. This short-term focus has obscured the evaluation of subsequent animal allergies (secondary LAA). We analyzed surveillance data from a 10-year LAA prevention program to estimate incidence rates of primary and secondary LAA and to evaluate the effectiveness of the prevention program in reducing the development of primary LAA. The 10-year incidence rates of primary and secondary LAA were 1.34 (95% CI, 0.78–1.90) and 11 (95% CI, 7.4–14.6) cases per 100 person-years, respectively. The annual incidence of primary LAA was reduced from 3.6% to 0 in the first 5 years and did not rise above 1.2% over the remaining years, whereas the incidence of secondary LAA was greater than 8% in most years. These findings suggest that programs effective at preventing primary LAA may need to be evaluated for their effectiveness at protecting against further risk.