Drug metabolism and toxicity during hypoxia.

Oxygen concentration affects the metabolism and toxicity of various drugs. A considerable amount of information is now available on the effects of hypoxia on the major pathways of drug metabolism, including oxidation (i.e., by cytochromes P-450, NAD+-dependent dehydrogenases, and monoamine oxidase), glucuronidation, sulfation, glutathione conjugation, glycine conjugation, and acetylation. Some pathways are essentially independent of O2 concentration while others are highly dependent upon O2. Certain drugs are activated to reactive and toxic metabolites by O2-dependent pathways. This aspect of drug toxicity serves as a basis for treatment of slow-growing solid tumors which have hypoxic regions that are resistant to chemo- and radiation therapies. Recent studies have also established that hypoxic cells have increased susceptibility to oxidative injury, and this can predispose cells to other pathological processes. However, in spite of the available knowledge concerning the O2 dependence of metabolism and toxicity of drugs, relatively little is known about the effects of chronic hypoxia on the expression of drug-metabolizing enzymes or upon the absorption, elimination, or toxicity of drugs. Thus, in addition to the information presently reviewed, major gaps exist in the knowledge needed to provide optimal drug therapy in the large population of patients who experience O2 deficiency. Comments and Perspectives. Specific basic research areas which need to be studied include the effects of hypoxia on drug absorption and elimination, the changes of neahypoxia that lead to enhanced susceptibility to drug toxicity, and the effects of chronic hypoxia on the metabolic systems involved in absorption, metabolism, and elimination of drugs. At an applied level, the available data on the O2 dependences of drug metabolism pathways need to be extended to examine in detail the O2 dependence to metabolism and toxicity of relevant, currently used therapeutic agents. Such efforts can be expected to continue to improve drug therapies and reduce toxicities in hypoxic patients.