Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the genetic polymorphism

Shon, Ji‐Hong; Yoon, Young‐Ran; Wang, Hong; Nguyen, Phuc Minh Chau; Lee, Sang-Seop; Choi, Young-Gil; Cha, In‐June; Shin, Jae‐Gook

doi:10.1016/j.clpt.2005.04.012

Cited by 71 publications

(47 citation statements)

References 36 publications

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“…On the other hand 3435CC genotype is associated with better prognosis and complete remission of acute myeloid leukemia (AML) [41] and higher predisposition to drug-resistant epilepsy [42]. Similar findings were obtained with fexofenadine in individuals with 3435TT/2677TT haplotype carriers [43], but some other authors failed to confirm this results for the same drugs [41,44]. 3435CC/2677GG haplotype has been indicated to be in significant correlation with higher response rate to docetaxel/cisplatin [45] treatment of non-small cell lung cancer.…”

Section: Discussionsupporting

confidence: 73%

Genotype Variability and Haplotype Profile of Abcb1 (Mdr1) Gene Polymorphisms in Macedonian Population

Naumovska

Nestorovska

Sterjev

et al. 2014

Prilozi

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The aim of this study was to evaluate the most common ABCB1 (MDR1, P-glycoprotein) polymorphisms in the population of R. Macedonia and compare the allele and haplotype frequencies with the global geographic data reported from different ethnic populations. The total of 107 healthy Macedonian individuals from the general population was included. Genotypes for the ABCB1 for three polymorphisms C1236T [rs1128503], G2677A/T [rs2032582] and C3435T [rs1045642] were analyzed by Real-Time PCR. Obtained allele frequencies for these three SNPs were similar to those observed in other European Caucasians. The detected genotype frequencies were 33.6% for 1236CC, 44.9% for 1236CT and 21.5% for 1236TT in exon 12; 32.7%, 44.9% and 22.4% for 2677GG, 2677GT and 2677GT consecutively in exon 21; and 25.2% for 3435CC, 52.3% for 3435CT and 22.5% for 3435TT in exon 26.Strong LD was observed in our study among all = 0.859, r 2 = 0.711). Eight different haplotypes were identified and the most prominent was the CGC haplotype (45.3%). Our study was the first to have documented the distribution of ABCB1 alleles, genotypes and haplotypes in the population of R. Macedonia. The obtained results can help in the prediction of different response to the drugs that are P-glycoprotein substrates. Additionally, in the era of individualized medicine the determination of the P-glycoprotein genotype might be a good predictive marker for determination of the subpopulations with higher risk to certain diseases.

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Section: Discussionsupporting

confidence: 73%

Genotype Variability and Haplotype Profile of Abcb1 (Mdr1) Gene Polymorphisms in Macedonian Population

Naumovska

Nestorovska

Sterjev

et al. 2014

Prilozi

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“…In contrast, P-gp polymorphisms may influence itraconazole to a far greater extent. This was demonstrated in a study in which itraconazole was administered before fexofenadine, a P-gp substrate, to individuals with either the T/T or the G/C phenotype (24). The AUC of fexofenadine was found to be significantly higher and CL/F to be significantly lower in individuals with the T/T phenotype than in individuals with the G/C haplotype, thus indicating greater P-gp inhibition by itraconazole in the T/T individuals.…”

Section: Discussionmentioning

confidence: 97%

“…In both studies, blood samples (4 ml each) for the determination of posaconazole plasma concentrations were collected on day Ϫ1 (blank sample); on day 1 at 2, 4, 5, 6, 8, and 12 h after the morning dose; and beginning on day 8 at 0 (predose), 2,4,5,6,8,12,24,48,72, and 96 h after the morning dose. Trough samples were collected on day 6 before the evening dose and on day 7 before the morning and evening doses.…”

Section: Methodsmentioning

confidence: 99%

Effects of Age, Gender, and Race/Ethnicity on the Pharmacokinetics of Posaconazole in Healthy Volunteers

Sansone-Parsons¹,

Krishna²,

Simon³

et al. 2007

Antimicrob Agents Chemother

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Posaconazole is a triazole antifungal for prophylaxis of invasive fungal infection and treatment of oropharyngeal candidiasis. We evaluated the effects of gender, age, and race/ethnicity (black or white) on the steady-state pharmacokinetics of posaconazole in two studies on healthy adult subjects (>18 years of age). Additionally, we explored the effect of P-glycoprotein expression and MDR1 genotype on posaconazole pharmacokinetics in black and white subjects. Age, gender, and race/ethnicity had no clinically relevant effects on posaconazole pharmacokinetics. No association was observed between any MDR1 single-nucleotide polymorphism and the area under the concentration-time curve for posaconazole. Posaconazole was safe and well tolerated regardless of age, gender, or race/ethnicity. In conclusion, age, gender, and race/ethnicity have no clinically relevant effects on the steady-state pharmacokinetics of posaconazole in healthy adults; therefore, dosage adjustments based on these covariates are unnecessary.

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“…FEX concentrations in plasma, brain, kidney, and liver were elevated significantly after oral and intravenous administration to P-gp-knockout mice (Cvetkovic et al, 1999). FEX has been used as a P-gp probe substrate for clinical drug-drug and food-drug interaction studies (Banfield et al, 2002;Shon et al, 2005).In rodents, FEX biliary excretion was not impaired in P-gp-or Bcrp-knockout mice or Mrp2-deficient Eisai hyperbilirubinemic rats (Tahara et al, 2005). These findings led to the hypothesis that one or more unidentified transport protein(s) distinct from P-gp, Mrp2, and Bcrp mediates the biliary excretion of FEX.…”

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confidence: 98%

mentioning

confidence: 99%

Multidrug Resistance-Associated Protein 2 Is Primarily Responsible for the Biliary Excretion of Fexofenadine in Mice

Tian¹,

Zamek‐Gliszczynski²,

Li³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Previous studies implicated P-glycoprotein (P-gp) as the major transport protein responsible for the biliary excretion of fexofenadine (FEX). However, FEX biliary excretion was not impaired in P-gp-or breast cancer resistance protein (Bcrp)-knockout mice or multidrug resistance-associated protein 2 (Mrp2)-deficient rats. The present study tested the hypothesis that species differences exist in the transport protein primarily responsible for FEX biliary excretion between mice and rats. Livers from Mrp2-knockout (Mrp2KO) mice and Mrp2-deficient (TR ؊ ) rats were perfused in a single-pass manner with 0.5 M FEX. N-(4-[2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (10 M) was employed to inhibit P-gp and Bcrp. FEX is a nonsedating H 1 receptor antagonist used clinically for the treatment of seasonal allergies. FEX is metabolically stable; less than 5% of the dose is eliminated by metabolism in humans (Cvetkovic et al., 1999). FEX is eliminated primarily via biliary excretion. In mice, biliary and renal clearances account for 50 to 70% and 10 to 20% of FEX total body clearance, respectively (Tahara et al., 2005).In vitro studies have demonstrated that cellular uptake of FEX is mediated by the 1A2 and 2B1 isoforms of human organic anion transporting polypeptide (OATP1A2 and OATP2B1, respectively); cellular efflux of FEX is mediated by human P-gp (Cvetkovic et al., 1999). FEX concentrations in plasma, brain, kidney, and liver were elevated significantly after oral and intravenous administration to P-gp-knockout mice (Cvetkovic et al., 1999). FEX has been used as a P-gp probe substrate for clinical drug-drug and food-drug interaction studies (Banfield et al., 2002;Shon et al., 2005).In rodents, FEX biliary excretion was not impaired in P-gp-or Bcrp-knockout mice or Mrp2-deficient Eisai hyperbilirubinemic rats (Tahara et al., 2005). These findings led to the hypothesis that one or more unidentified transport protein(s) distinct from P-gp, Mrp2, and Bcrp mediates the biliary excretion of FEX. Recent studies have suggested that species differences exist in transport mechanisms mediating biliary excretion (Zamek-Gliszczynski et al., 2006b). The purpose of this work was to determine whether Mrp2 is responsible for FEX biliary excretion in mice and whether species differences in FEX biliary excretion exist between mice and rats. Furthermore, the involvement of transport mechanisms other than Mrp2, P-gp, and Bcrp in FEX biliary excretion was investigated by using the P-gp and Bcrp inhibitor N- (4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) in Mrp2-knockout mice.

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Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the genetic polymorphism

Abstract: The effect of MDR1 G2677T/C3435T haplotypes on fexofenadine disposition are magnified in the presence of itraconazole. Itraconazole pretreatment significantly altered the disposition of fexofenadine and thus its peripheral antihistamine effects.

Cited by 71 publications

References 36 publications

Genotype Variability and Haplotype Profile of Abcb1 (Mdr1) Gene Polymorphisms in Macedonian Population

Genotype Variability and Haplotype Profile of Abcb1 (Mdr1) Gene Polymorphisms in Macedonian Population

Effects of Age, Gender, and Race/Ethnicity on the Pharmacokinetics of Posaconazole in Healthy Volunteers

Multidrug Resistance-Associated Protein 2 Is Primarily Responsible for the Biliary Excretion of Fexofenadine in Mice

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