# NEUTROPHIL MEDIATED DRUG TOXICITY IN THE ELDERLY

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 1993 · $226,012

## Abstract

DESCRIPTION (Adapted from the Applicant's Abstract):  Certain medications
for degenerative diseases (such as atherosclerosis and cardiac arrhythmias)
associated with aging can cause serologic abnormalities characteristic of
an autoimmune diathesis.  Some of these patients may go on to develop
symptoms of a lupus-like syndrome, necessitating discontinuation of
therapy.  The overall goals of this project are to determine the cause of
this and other forms of chronic toxicity, and the basis for the variable
sensitivity of the patient population.  The premise of this proposal is
that some forms of idiosyncratic drug toxicity are not directly due to the
ingested parent compound but may be related to reactive drug metabolites,
generated in vivo.  Based on the precedent established with procainamide
metabolism, it is proposed that activated neutrophils may be primary
mediators in oxidizing certain drugs to reactive forms.  Preliminary data
suggest that this mechanism may, in fact, be applicable to metabolism of
other drugs.  Reactive products will be detected using a bioassay for
cytotoxicity of cells in culture, chromatographically separated and
identified by spectrophotometric and mass spectrometric analyses.  These
studies will determine the chemical prerequisites for drug susceptibility
to neutrophil-mediated metabolic reactions.  The mechanisms for these
transformations will be determined by the use of specific inhibitors and
competitors of the extracellular oxidative machinery of neutrophils, by
using neutrophils from patients with well-defined genetic lesions in
components of this pathway and a cell-free system which models the
oxidative reactions.  The cell-free system will also provide a convenient
assay for screening new drugs for susceptibility to neutrophil-mediated
transformations.  Capacity of neutrophils to generate reactive drug
metabolites will be evaluated in patients with a history of drug-induced
autoimmunity, in asymptomatic drug users and in normal donors of various
ages.  These studies will identify functional polymorphisms in neutrophil
oxidative machinery and determine if increasing age exacerbates drug
metabolism by this mechanism.  Mouse models will be developed in which the
test drug is continuously infused from implanted osmotic pumps, creating a
uniform and long-term exposure regimen at drug levels comparable to that of
human subjects.  This system is intended to facilitate identification of in
vivo-generated metabolites recognized by drug-specific lymphocytes and
allow further exploration of the pathogenesis of chronic drug toxicity.

## Key facts

- **NIH application ID:** 3121455
- **Project number:** 5R01AG009574-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **SAM.gov UEI:** PHZJFZ32NKH4
- **Principal Investigator:** ROBERT L RUBIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $226,012
- **Award type:** 5
- **Project period:** 1991-02-01 → 1996-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3121455

## Citation

> US National Institutes of Health, RePORTER application 3121455, NEUTROPHIL MEDIATED DRUG TOXICITY IN THE ELDERLY (5R01AG009574-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3121455. Licensed CC0.

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