Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

Ja, Williams; Ring, Barbara J.; Cantrell, Varon E.; Jones, David R.; Eckstein, James A.; Ruterbories, Kenneth J.; Hamman, Mitchell A.; Hall, Stephen D.; Wrighton, Steven

doi:10.1124/dmd.30.8.883

Cited by 416 publications

(375 citation statements)

References 17 publications

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“…2, 8,9 Although few common CYP3A4 polymorphisms have been identified with in vivo effect on enzyme activity, CYP3A5 expression is strongly correlated with a single-nucleotide polymorphism (SNP) within intron 3 (6986A4G; CYP3A5*3). 10 This allele is prevalent among Japanese individuals, 11 suggesting that germline CYP3A5 SNPs may influence IM trough concentration and drug efficacy in this population.…”

Section: Introductionmentioning

confidence: 99%

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

et al. 2010

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Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P¼0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P¼0.015). Moreover, previous studies have shown that the ABCG2 421C4A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C4A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.

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Section: Introductionmentioning

confidence: 99%

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

et al. 2010

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“…No dose adjustment is required in the setting of renal impairment, because SMV is eliminated by the liver [85] . SMV is well tolerated, and adverse reactions in patients receiving SMV in combination with PEG-IFN-α [86] . Coadministration of SMV with inhibitors of cytochrome P450 3A (CYP3A) is not recommended.…”

Section: Second-generation Pismentioning

confidence: 99%

“…NPIs: Nucleoside polymerase inhibitors; NNPIs: Non-nucleoside polymerase inhibitors; DAA: Direct acting antiviral. [86] . Coadministration of SMV with inhibitors of cytochrome P450 3A (CYP3A) is not recommended.…”

Section: Smvmentioning

confidence: 99%

Chronic hepatitis C: This and the new era of treatment

Bertino

Ardiri

Proiti

et al. 2016

WJH

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Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects. Core tip: This review analyzes the current therapies for chronic hepatitis C and the future challenges of the research. So it tries to give an update on the research of hepatitis C virus (HCV) infection, providing a critical view of the emerging therapies and their impact on the future management of HCV infection. Since novel TOPIC HIGHLIGHT Chronic hepatitis C: This and the new era of treatment2016 Hepatitis C Virus: Global view treatments for HCV infection are highly efficacious but costly, priority should be given to patients with advanced hepatic fibrosis, which is a disease that cannot be deferred. INTRODUCTIONThe hepatitis C virus (HCV), identified in the 70s but cloned in 1989, is a single-stranded RNA virus belonging to the family Flaviviridae.HCV is the main cause of progressive liver diseases and a public health problem worldwide. It is estimated that approximately 150-180 million people in the world are living with chronic hepatitis [1,2] , 350 million of whom die each year from liver damage associated with the infection [3] . About 80% of people infected with HCV develop chronic hepatitis, of which 20%-40% will develop liver cirrhosis or hepatocellular carcinoma (HCC) 20-30 years after infection.As a consequence, chronic HCV infection is the major reason of liver transplantation in developed countries [4][5][6][7] . According to the Global Burden Disease Study in Europe, the death rate for viral hepatitis is significantly higher than that for human immunodeficiency virus (HIV) and acquired immune deficiency syndrome; in particular in 2010, the number of deaths from viral hepatitis have been ten times bigger than that attributed to HIV. It is reasonable to think that this difference is due to the lack of effective therapies for HCV until a few years ago [8] .HCV is also one of the main causes of death [9] . The virus causes both liver damage and extra-hepatic manifestations, many of these syndromes are associated with the ability of HCV to replicate in peripheral blood mononuclear cells (PBMCs); an example is the mixed cryoglobulinemia, which is by far the most common extrahepatic disease closely connected with the infection.Recently it was shown that antiviral treatment is associated with improved renal and cardiovascular outcomes in patients with cryoglobulinemia [4,6,10,11] . Newly approved oral anti-HCV drugs are very safe and effective, but unfortunately their cost will force to choose a priority of treatment. The intent should therefore be to identify and treat patients with a higher risk of morbidity and mortality due to HCV.The availability of these new oral treatments can definitely heal patients and ...

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“…CYP3A accounts for approximately 60% of the total cytochrome content in the liver. Nearly half of all current clinical drugs are substrates for CYP3A [1,2] . Overall, the activity of the CYP3A subfamily in adults is comprised mostly of CYP3A4 and CYP3A5 [2] .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism

Luo

et al. 2009

Acta Pharmacol Sin

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Aim: Currently, there is considerable debate as to which method is more accurate for measuring the activity of CYP3A in vivo: cortisol 6β-hydroxylation clearance (Cl m(6β) ) or the urinary ratio of 6β-OHF to F (6β-OHF/F). Furthermore, the value of measuring endogenous levels of cortisol over a 24 h period (AUC F ) needs to be confirmed. The aim of the present study was to determine which method was most effective at measuring changes in the in vivo activity of CYP3A: AUC F , Cl m(6β) , or 6β-OHF/F. Methods: A two phase, cross-over design was adopted in this study. A total of 24 subjects (12 males and 12 females) were randomly assigned to one of two groups: the test group subjects were given 250 mg clarithromycin tablets twice a day for a period of 4 d, whereas the control group received a placebo twice daily for a similar period. On d 5 of the study, the last dose of either clarithromycin or placebo was supplemented with an oral dose of 7.5 mg midazolam (MDZ); blood and urine samples were then collected at various times. All samples collected at the same sampling times on d 4 were used to evaluate the effects of MDZ administration on cortisol levels and metabolism. The ratio of 1-hydroxymidazolam (1-OHMDZ) concentration to MDZ concentration at 1 h (MR) was taken as a measure of the in vivo CYP3A activity. AUC F , Cl m(6β) , and 6β-OHF/F were also used as biomarkers for CYP3A activity. Results: No correlations were found (either before or after inhibition) between CYP3A activity and any of the following measures: AUC F , Cl m(6β) , or 6β-OHF/F (r<0.4, P>0.05). After 4 d of clarithromycin administration, CYP3A activity (MR) decreased by 75% (P=0.000), whereas AUC F increased by 19% (P=0.040), and Cl m(6β) and 6β-OHF/F decreased by 54.2% (P=0.000) and 50% (P=0.003), respectively. No significant changes in AUC F (P=0.178), or in the amount of urinary 6β-OHF (P=0.169), or in F (P=0.391) were found over a 24 h time period, either with or without MDZ administration. Conclusion: Although Cl m(6β) and 6β-OHF/F can reflect the decline in CYP3A activity, the impression they provide is neither accurate nor complete. AUC F is completely ineffective for evaluating variations in CYP3A activity. MDZ administration had no evident effects on either cortisol metabolism or excretion over a period of 24 h.

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Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

Cited by 416 publications

References 17 publications

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

Chronic hepatitis C: This and the new era of treatment

Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism

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