5. Discussion and perspectives
Hypoxia alters the expression and activity of CYPs in vivo and has several effects on humans. As important exogenous and endogenous metabolic enzymes, changes in CYP under hypoxic conditions lead to changes in drug metabolism kinetics and mediate changes in endogenous metabolites. Changes in drug metabolism kinetics suggest that the dosage of drugs should be adjusted under high-altitude hypoxia, while changes in endogenous compounds play an important role in the regulation of physiological levels under hypoxia and the occurrence of pathological conditions of high-altitude diseases, some of which may play a beneficial role in facilitating the adaptation of the organism to hypoxia. Therefore, exploring the relationship between CYP metabolites and high-altitude disease is not only beneficial for assessing the occurrence and development of high-altitude diseases, but also provides a new approach for targeting the treatment of hypoxic diseases.
The effect of hypoxia on drug metabolism has been a popular topic in plateau medicine in recent years. The current study concludes that the metabolism and CL of most drugs are slowed, and the duration of action is prolonged in vivo under hypoxia. However, the metabolism of some drugs, such as aminophylline, caffeine, norfloxacin, and cloxartan, is accelerated under hypoxia, suggesting that the plain drug regimen may not be fully applicable to the plateau. However, clinicians and patients may not be aware of these issues and continue to follow a plain dosing regimen. This review hopes to provide clinicians and patients with some feasible dosing suggestions by reviewing the changes in pharmacokinetics under hypoxia at the plateau:
  1. The duration of hypoxia at plateau has the most important effect on the metabolic kinetics of the drugs and different altitudes have different effects, therefore, clinicians should expand the pre-dose counselling for patients, including the length of time that high-altitude travelers were plateau and altitude locations to establish specific drug administrations.
  2. For drugs whose metabolism is slowed by hypoxia, the dose may be appropriately reduced, the interval between doses extended, and the frequency of administration reduced, with reference to the administration protocols of lowland areas. For drugs with faster metabolism, the dose should be increased, the interval between doses should be shortened, and the frequency of administration should be increased to improve the safety and efficacy of the drugs. For some drugs that have not yet been studied, attention should be paid to the timely observation of the therapeutic efficacy of the drugs and the adverse effects of the drugs.
  3. Minority groups congregate in plateaus, and due to genetic differences between different ethnic groups and different habits, there are genetic polymorphisms in CYP enzymes, which further cause differences in drug metabolism. This further causes differences in drug metabolism; therefore, different drug administration protocols should be formulated for individual living on the plateau according to different ethnic groups.
  4. For high-altitude travelers, drugs should not be used blindly for prevention but should be assessed to confirm the risk of entering the plateau and patients should consult with a doctor about the use of drugs; and transition to different altitudes as necessary to facilitate organismal hypoxic acclimatization.
The involvement of CYPs in the endogenous metabolism, particularly in the lungs, brain, and heart, has received increasing attention. Hypoxia in high-altitude environments affects the lungs, brain, and heart, and although a growing body of research has recognized the relative contribution of CYP and their metabolites to hypoxia-related diseases, only a few of these diseases are well understood; in particular, the role of CYPs has been demonstrated in HAPH. We hypothesized that the CYP system under hypoxia might be involved in the physiological pathology of altitude sickness by regulating vascular tone, promoting angiogenesis, and controlling inflammatory responses. Changes in CYP and their metabolites in hypoxic diseases can be used as markers for the development of hypoxic diseases and targets for their treatment of hypoxic diseases. In addition, changes in CYP activity under hypoxia can be assessed by changes in endogenous metabolites, which means that the activities of different CYP enzyme isoforms can be predicted by determining the concentration of certain compounds in the urine or blood without the need to introduce exogenous compounds. Although numerous studies have been conducted on the role of CYPs in the pathological process of hypoxic diseases, the effects of hypoxia on the organism are complex and protracted. Clinical studies on CYP-regulated pathways in various diseases are still lacking and more research is needed to elucidate their biological, molecular, and cytological roles in the regulation of hypoxia-associated pathophysiological processes. Meanwhile, the possibility of using CYP450 mimics or antagonists or regulating the expression of sEH enzymes and cyclooxygen metabolites in hypoxic environments as a new approach to treating hypoxia-associated lung, brain, and heart injury may be urgent research to be addressed in the future.
Recently, many studies have been conducted on CYP under plateau hypoxia, but these current studies mainly focus on pharmacokinetic studies of some common drugs. However, co-administration is mostly used in the clinic, and there are few studies on whether hypoxia affects drug-drug interactions. Although this review suggests that the dosage of drugs under plateau hypoxia based on the results of the current study, drug metabolism studies under plateau hypoxia are still in the exploratory stage, and due to the variability of the modeling conditions and study subjects, the current studies have not yet reached a unified conclusion. Additionally, there are few examples of how hypoxia-induced changes in CYP affect changes in drug response, and conducting joint studies on changes in drug metabolism kinetics and pharmacodynamics under hypoxia is also a key focus for future research in personalized medicine. Recently, new models such as PBPK, liver microarray, CRISPR-Cas9, and molecular modeling have been gradually applied to drug metabolism research. Future research should adopt more methods, not only to better illustrate the mechanism of CYP changes under hypoxia in plateau conditions, but also to study the changes in pharmacodynamics and toxicity caused by changes in drug metabolism kinetics in hypoxia.