First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele

O’Brien, Travis J.; Kidd, Robert S.; Richard, Craig A. H.; Ha, Ngoc T; Witcher, Preston; Tran, Linda V.; Barbour, April; Tuck, Matthew; McIntosh, Samantha; Douglas, Jacqueline N.; Harralson, Arthur F.

doi:10.1016/j.cca.2013.05.008

Cited by 6 publications

(6 citation statements)

References 26 publications

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“…For example, the C max of SMV ranged from 1.8 to 13.5 M (n ϭ 123, HPC3003 clinical trial in Japan). This range could be further expanded as the patient population increases, partially because of the presence of rare variants in the drug-metabolizing and transporter genes (26,27). Second, although E 2 G and CCK-8 have been considered good surrogate probes for use in OATP1B inhibition studies (9,23), the R value obtained from other OATP1B substrates may be different from the values obtained in this study, as exemplified by the report showing that the IC 50 values of rifamycin SV toward OATP1B1-mediated E 2 G and rosuvastatin uptake are 0.34 Ϯ 0.05 and 0.05 Ϯ 0.02 (M), respectively (23).…”

Section: Discussionmentioning

confidence: 99%

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Furihata

Matsumoto

et al. 2014

Antimicrob Agents Chemother

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b Simeprevir (SMV), asunaprevir (ASV), daclatasvir (DCV), and sofosbuvir (SFV), which are newly developed direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection, are among the key components of anti-HCV regimens. Preclinical studies have identified inhibitory properties for some of these DAAs against organic anion transporting polypeptide 1B (OATP1B) functions. However, their details remain mostly uncharacterized. Because OATP1B1 and OATP1B3 play determinant roles in the pharmacokinetics of various drugs via their uptake into human hepatocytes, it is plausible that the inhibition of these OATP1Bs by a DAA would create a potential risk of drug-drug interaction, which has been an emerging concern in anti-HCV therapy. Accordingly, in the present study, we intended to clarify the inhibitory characteristics of newly developed DAAs toward OATP1B1 and -1B3 functions. The results of our coincubation inhibition assays have shown that all tested DAAs could inhibit OATP1B1 functions and that SMV, ASV, and DCV (to a lesser extent), but not SFV, exhibited long-lasting preincubation inhibitory effects on OATP1B1 functions. It was also found that the preincubation inhibitory effects of SMV and ASV could augment their coincubation inhibition potency. Furthermore, significant, but differential, inhibitory effects of the DAAs on the OATP1B3 function were identified. To summarize, our results clearly show that the newly developed DAAs are newly identified OATP1B1 and OATP1B3 inhibitors with distinctive interaction properties. It is believed that these inhibition profiles will provide essential information to all concerned parties with respect to the clinical significance of DAA-mediated inhibition of OATP1Bs in anti-HCV therapy.

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Section: Discussionmentioning

confidence: 99%

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Furihata

Matsumoto

et al. 2014

Antimicrob Agents Chemother

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“…They have been identified as the most common defective alleles and have exhibited reduced metabolic activities, both in vitro and in vivo, for the CYP2C9 substrates, such as warfarin. In addition to these two common alleles, other allelic variants, such as CYP2C9*4 (Lee et al, 2007), CYP2C9*5 (Dickmann et al, 2001), CYP2C9*8 (Liu et al, 2012), CYP2C9*11 (Tai et al, 2005), CYP2C9*12 (O'Brien et al, 2013), CYP2C9*14 (Lee et al, 2014), CYP2C9*35 (Ciccacci et al, 2011), CYP2C9*57 (Nahar et al, 2013), and CYP2C9*58 (Luo et al, 2014), were reported to affect warfarin sensitivity. In this study, we present the case of a Chinese warfarin-sensitive patient who requires only one-half of the normal oral warfarin dose.…”

Section: Introductionmentioning

confidence: 99%

Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C959*

Dai

Wang

et al. 2015

Drug Metab Dispos

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CYP2C9, one of the most important drug-metabolizing enzymes, is responsible for metabolizing approximately 15% of clinically important drugs, including warfarin, diclofenac, and losartan. Similar to other CYP members, human CYP2C9 exhibits marked genetic polymorphisms among individuals of different ethnicities. In this study, a novel missense mutation (1300A>T) was identified in a warfarin-sensitive patient after a genetic screen of three candidate genes related to high variability in response to warfarin doses. This base transversion leads to an Ile-toPhe amino acid substitution at codon 434 within the CYP2C9 protein, and this new variant has been named a novel allele, CYP2C9*59, by the Human CYP Allele Nomenclature Committee (http://www.cypalleles.ki. se/cyp2c9.htm). The exogenous expression of CYP2C9.59 in insect cell microsomes revealed that, despite a similar protein expression level as wild-type CYP2C9, variant CYP2C9.59 exhibited significantly reduced maximal velocity, V max , and/or increased Michaelis constant, K m , values toward three CYP2C9-specific substrates. Our data suggest that the 1300A>T mutation can greatly decrease the enzymatic activity of the CYP2C9 protein both in vitro and in vivo. IntroductionCYP2C9 is the major CYP2C isoform in humans and is responsible for the metabolism of approximately 15% of all clinically important drugs (Samer et al., 2013;Chen et al., 2014). Similar to other CYP members, CYP2C9 is highly polymorphic across various racial and ethnic populations. These genetic polymorphisms have been shown to have clinical importance, leading to great inter-individual variability and serious adverse effects in the efficacies of many therapeutic drugs (Chaudhry et al., 2014). Alleles CYP2C9*2 (containing a R144C substitution) and CYP2C9*3 (containing an I359L substitution) have been well studied among different ethnic populations. They have been identified as the most common defective alleles and have exhibited reduced metabolic activities, both in vitro and in vivo, for the CYP2C9 substrates, such as warfarin. In addition to these two common alleles, other allelic variants, such as CYP2C9*4 ( Lee et al., 2007) Nahar et al., 2013), and CYP2C9*58 (Luo et al., 2014), were reported to affect warfarin sensitivity. In this study, we present the case of a Chinese warfarin-sensitive patient who requires only one-half of the normal oral warfarin dose. Genetic analysis in that patient revealed an absence of the common mutations in CYP2C9 (*2, *3), VKORC1 (rs9923231 and rs7294), and CYP4F2 (rs2108622) that are usually related to warfarin sensitivity. However, a novel missense mutation (1300A.T) was identified in exon 9 of the CYP2C9 gene. The in vitro functional assessment of this newly found CYP2C9 variant revealed that the substitution of an Ile to a Phe at codon 434 significantly reduced the enzymatic activity of this variant toward all of the tested substrates. Materials and MethodsStudy Subject. The study subject was a 47-year-old male Han Chinese patient who has taken warfarin...

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“…The allele rs9332239 corresponds to the rarer CYP2C9*12 (P489S) allele observed in 0.2% of the population which has also been shown to result in reduced enzymatic activity. Patients with the CT genotype, like our patient, may have decreased metabolism of tolbutamide compared to homozygous reference individuals (14,15). Taken together, the variants in CYP2C9 identified in patient III.1 may explain her hypoglycemic response to standard sulfonylurea treatment due to reduced drug metabolism by impaired CYP2C9 enzymatic activity.…”

Section: Discussionmentioning

confidence: 59%

KCNJ11 Mutation in One Family is Associated with Adult-Onset Rather than Neonatal-Onset Diabetes Mellitus

Breidbart

Golden

Gonzaga‐Jauregui

et al. 2018

AACE Clinical Case Reports

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Objective: To present a case of adult-onset familial diabetes mellitus in which a genetic etiology typical for neonatal diabetes was identified. Methods: We conducted whole-exome and Sanger sequencing, assessed clinical presentation and family history, and performed a literature review. Results: A 40-year-old, thin woman presented with a 10-year history of mildly elevated fasting glucose and A1C levels. Her mother had diabetes mellitus since her 40s and is on insulin, and her daughter presented with diabetes mellitus at age 21. The patient and her daughter underwent whole-exome sequencing and were found to have a mutation in the KCNJ11 gene, c.G685A, p.E229K. This mutation is known to be associated with neonatal presentation of diabetes mellitus, which neither of these family members had a history of. Given her known mutation and postpran-dial hyperglycemia, a trial of low-dose sulfonylurea was initiated in the daughter but failed due to hypoglycemia. She was found to have a CYP2C9 genotype associated with poor oral drug clearance. Conclusion: KCNJ11 mutation should be screened for in patients and families meeting criteria for maturity-onset diabetes of the young, even without evidence of neonatal onset in the family. Furthermore, even though sulfonylurea therapy is successful in the majority of patients with KCNJ11 mutations, there may be a role for other interacting environmental or genetic modifiers, such as CYP2C9 genotype, that affect sulfonylurea metabolism. Those patients who have delayed onset of disease and milder courses may be less ideal candidates for this treatment. (AACE Clinical Case Rep. 2018;4:e411-e414) Abbreviations: BMI = body mass index; KATP = ATP-sensitive potassium channel; MODY = maturity-onset diabetes of the young; NDM = neonatal diabetes mellitus

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First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele

Cited by 6 publications

References 26 publications

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C959*

KCNJ11 Mutation in One Family is Associated with Adult-Onset Rather than Neonatal-Onset Diabetes Mellitus

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First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele

Cited by 6 publications

References 26 publications

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C9*59

KCNJ11 Mutation in One Family is Associated with Adult-Onset Rather than Neonatal-Onset Diabetes Mellitus

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Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C959*