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:
- 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.
- 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.
- 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.
- 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.