Respiratory tract uptake of inhalants and metabolism of xenobiotics.
The combined impact of new research regarding the dosimetry of inhalants, discussed in early paragraphs of this review, and the rapidly developing knowledge regarding the location and substrate specificities of the enzymes responsible for xenobiotic metabolism should soon lead to new insights into the causes and prevention of cancer and other diseases of the respiratory tract and may provide insight into the design of drugs used in the treatment of respiratory tract disease. Among the developments to be expected within the next decade are the following: 1. The issue of extrapulmonary versus intrapulmonary activation of lung prodrugs and protoxicants will be resolved by validation of the different dosimetries predicted for highly lipophilic inhalants compared to less lipophilic ones. 2. The possibly complex roles of P450 isozymes 1A1 and 2D6 and other forms in the causation of human lung cancer will undoubtedly be better understood in the next few years. 3. Interspecies comparisons of respiratory tract enzyme activities--both activating and detoxicating--will lead to improved use of laboratory animals as models for expected toxicological and pharmacological effects in humans. 4. The potential role of nasal uptake and metabolism in causing brain disease will be established or denied experimentally. 5. The complex relationships between host factors--such as hormone levels and the presence of inflammation--and metabolism-mediated toxicity will become clearer. 6. As new research results continue to illuminate the complexities of the interactions of xenobiotics with respiratory tract tissue, clues as to how best to administer drugs via the respiratory tract and understanding of changes in disease patterns--such as the recent shift in sites for lung cancer--will follow.
Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185.
A R
AR
Dahl
J L
JL
Lewis
D000336:Aerosols / Q000493:pharmacokinetics*; D000818:Animals; D006801:Humans; D012137:Respiratory System / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism* / Q000493:pharmacokinetics
D000336:Aerosols; D015262:Xenobiotics