Fluticasone Propionate Pharmacogenetics: CYP3A4*22 Polymorphism and Pediatric Asthma Control

Abstract

Objective To determine the relationship between allelic variations in genes involved in fluticasone propionate (FP) metabolism and asthma control among children with asthma managed with inhaled FP. Study design The relationship between variability in asthma control scores and genetic variation in drug metabolism was assessed by genotyping nine single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and CYP3A7. Genotype information was compared with asthma control scores (0 = well-controlled to 15 = poorly-controlled), determined by using a questionnaire modified from the National Heart Lung and Blood Institute Expert Panel 3 guidelines. Results Our study cohort was comprised of 734 children with asthma (mean age 8.8 ± 4.3 years), who were predominantly male (61%) and non-Hispanic Whites (53%); 413 children (56%) were receiving inhaled glucocorticoids daily, of which FP was prescribed most frequently (65%). Among the children receiving daily FP, SNPs in the genes CYP3A5 and CYP3A7 were not associated with asthma control scores. In contrast, asthma control scores were significantly improved among 20 (7%) children with the CYP3A4*22 allele (median 3, range 0-6), as compared with the 201 patients without the CYP3A4*22 allele (median 4, range 0-15) (P=0.02). The presence of CYP3A4*22 was associated with improved asthma control scores by 2.1 points (95% CI: 0.5-3.8). Conclusions The presence of CYP3A4*22, which is associated with decreased hepatic CYP3A4 expression and activity, was accompanied by improved asthma control among FP treated children. Decreased CYP3A4 activity may improve asthma control with inhaled FP.

Metabolism of Beclomethasone Dipropionate by Cytochrome P450 3A Enzymes

“…In support of this idea, a recent publication by Stockmann et al (2013) demonstrated that the expression of the CYP3A4*22 allele, which codes for an inactive enzyme in the liver (Elens et al, 2011a(Elens et al, ,b, 2012(Elens et al, , 2013Kitzmiller et al, 2013), coupled with treatment of these patients with the CYP3A4 and 3A5 mechanism-based inhibitor fluticasone propionate (Murai et al, 2010), correlated with improved asthma control. As such, a decrease in CYP3A-mediated metabolism of fluticasone propionate (and possibly other glucocorticoids) in the lung and liver may increase the bioavailability of the active drug in the lung, leading to greater efficacy.…”

Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma

“…A description of the study population is provided in the online supplement. DNA was extracted as previously described (27).…”

“…Each patient's level of chronic asthma control was determined using a questionnaire (Table E2) based upon guidelines modified from the National Heart Lung and Blood Institute Expert Panel Report 3 (28) as described by Stockmann and colleagues (27). Each subject's asthma control score was calculated as the sum of all five question in Table E2, providing a score ranging from 0 (optimally controlled) to 15 (poorly controlled).…”

The Influence of the CYP3A4*22 Polymorphism and CYP2D6 Polymorphisms on Serum Concentrations of Aripiprazole, Haloperidol, Pimozide, and Risperidone in Psychiatric Patients

“…19 The CYP3A4*22 allele has a relatively high frequency, ranging from 3.2% to 6.9% in the white population. [19][20][21][22][23][24] CYP3A4*22 appears to be the most promising CYP3A4 SNP reported so far. We showed before higher serum concentrations of quetiapine, an antipsychotic mainly metabolized by CYP3A4, in carriers of the CYP3A4*22 allele.…”

“…20,21,26 Lopinavir displayed lower clearance and higher trough concentrations in CYP3A4*22/*22 HIV-positive patients, 23 and presence of the CYP3A4*22 allele was accompanied by improved asthma control in fluticasone propionate-treated children. 22 For paclitaxel, even without an association of CYP3A4*22 with pharmacokinetic parameters, female carriers of *22 appeared to be at risk of developing grade 3 neurotoxicity, 27 a result of a decreased cytoprotective effect against toxic substrates by CYP3A4 expressed in peripheral nerves. 28 Aripiprazole, haloperidol, pimozide, and risperidone are frequently prescribed antipsychotics in the psychiatric hospital GGz Centraal located in Veldwijk, Ermelo, The Netherlands.…”