Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes

Song, Yurong; Li, Chenxi; Liu, Guangzhi; Li, Rui; Chen, Youwen; Li, Wen; Cao, Zhiwen; Zhao, Baosheng; Lü, Cheng; Liu, Yuanyan

doi:10.1007/s40262-021-01001-5

Cited by 49 publications

(32 citation statements)

References 164 publications

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“…Лекарство при этом, как правило, превращается в неактивный или менее активный метаболит. Приблизительно 80% всех реакций окислительного метаболизма лекарственных препаратов происходит с участием одного или нескольких ферментов цитохрома Р450 (из семейств цитохромов 1-3), на долю которого также приходится половина всех реакций по элиминации лекарств из организма [15].…”

Section: метаболизмunclassified

“…Ингибирование этих ферментов обычно ведет к увеличению концентрации препарата в крови и усилению его действия (как терапевтического, так и побочного). И, напротив, индукция ферментов служит причиной ускоренного метаболизма лекарственного препарата и снижения эффективности и длительности его действия [11,15].…”

Section: метаболизмunclassified

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Basic principles of combination therapy: focus on drug-drug interaction

Martsevich¹,

Lukina²,

Драпкина³

2021

Cardiovasc Ther Prev

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The article is devoted to the issue of drug interactions in the combination regimens. Today, when drug therapy is the first-line approach for patients with noncommunicable diseases, and the world population ageing leads to an increase in the number of patients with severe comorbidity and polypharmacy, the problem of drug-drug interaction is especially relevant. The article discusses the main types of drug interactions — pharmacokinetic (related to absorption, distribution, metabolism and excretion of drugs) and pharmacodynamic ones, leading to synergy or antagonism of the pharmacological effects. The consequences of drug interactions can be desirable and undesirable, while the latter are much more common. Attention should be directed precisely to preventing such interactions. Also, using data from special scales and lists (Beers criteria, STOPP/START criteria), the options for various adverse drugdrug interactions are briefly described. In addition, the article provides a number of Internet resources that allow assessing the drug interaction risk when prescribing combination therapy.

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Section: метаболизмunclassified

Basic principles of combination therapy: focus on drug-drug interaction

Martsevich¹,

Lukina²,

Драпкина³

2021

Cardiovasc Ther Prev

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“…Cytochrome P450 (CYP) enzymes are members of the superfamily of heme-containing monooxygenases that catalyze the metabolism of endogenous substances (e.g., steroids, monoaminergic neurotransmitters, arachidonic acid, bile acids) and the majority of clinically important drugs including psychotropics (neuroleptics, antidepressants, anxiolytics) [ 1 , 2 ]. The CYP enzymes are located primarily in the endoplasmic reticulum of hepatic cells.…”

Section: Introductionmentioning

confidence: 99%

“…The CYP enzymes are located primarily in the endoplasmic reticulum of hepatic cells. Among various CYP enzymes, CYP1, CYP2 and CYP3 are three major families that are involved in the metabolism of approximately 90% of drugs on the market [ 2 ]. Drugs that can inhibit or induce the metabolic activity of the CYP enzymes have the potential to affect the metabolism of concomitantly administered drugs, and to lead to changes in their efficacy or to increase the risk of adverse effects [ 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms

2021

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Therapy of schizophrenia requires long-term treatment with a relevant antipsychotic drug to achieve a therapeutic effect. The aim of the present study was to investigate the influence of prolonged treatment with the atypical neuroleptic asenapine on the expression and activity of rat cytochrome P450 (CYP) in the liver. The experiment was carried out on male Wistar rats. Asenapine (0.3 mg/kg s.c.) was administered for two weeks. The levels of CYP mRNA protein and activity were determined in the liver and hormone concentrations were measured in the pituitary gland and blood serum. Asenapine significantly decreased the activity of CYP1A (caffeine 8-hydroxylation and 3-N-demethylation), CYP2B, CYP2C11 and CYP3A (testosterone hydroxylation at positions 16β; 2α and 16α; 2β and 6β, respectively). The neuroleptic did not affect the activity of CYP2A (testosterone 7α-hydroxylation), CYP2C6 (warfarin 7-hydroxylation) and CYP2E1 (chlorzoxazone 6-hydroxylation). The mRNA and protein levels of CYP1A2, CYP2B1, CYP2C11 and CYP3A1 were decreased, while those of CYP2B2 and CYP3A2 were not changed. Simultaneously, pituitary level of growth hormone-releasing hormone and serum concentrations of growth hormone and corticosterone were reduced, while that of triiodothyronine was enhanced. In conclusion, chronic treatment with asenapine down-regulates liver cytochrome P450 enzymes, which involves neuroendocrine mechanisms. Thus, chronic asenapine treatment may slow the metabolism of CYP1A, CYP2B, CYP2C11 and CYP3A substrates (steroids and drugs). Since asenapine is metabolized by CYP1A and CYP3A, the neuroleptic may inhibit its own metabolism, therefore, the plasma concentration of asenapine in patients after prolonged treatment may be higher than expected based on a single dose.

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“…The individual impact and clinical significance of genetic factors on drug metabolism have been well established in vivo and in vitro [ 1 , 2 , 3 , 4 , 5 ]. Several gene-coding alleles for drug-metabolizing enzymes and transporters correspond to distinct phenotypes [ 6 , 7 ], making it necessary to account for distinctive environmental factors and inter-individual genetic differences while establishing rational prescribing decisions to ensure an optimal pharmacological response.…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of 21 Rare Allelic CYP1A2 Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin O-Deethylation

Kumondai

Rico

Hishinuma

et al. 2021

JPM

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Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin O-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants.

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Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes

Cited by 49 publications

References 164 publications

Basic principles of combination therapy: focus on drug-drug interaction

Basic principles of combination therapy: focus on drug-drug interaction

The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms

Functional Characterization of 21 Rare Allelic CYP1A2 Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin O-Deethylation

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