The role of CYP2C9*2, CYP2C9*3 and VKORC1-1639 variants on the susceptibility of upper gastrointestinal bleeding: A full case-control study

Forgerini, Marcela; Urbano, Gustavo; Nadai, Tales Rubens de; Batah, Sabrina Setembre; Fabro, Alexandre Todorovic; Mastroianni, Patrícia de Carvalho

doi:10.3389/jpps.2023.11136

Cited by 5 publications

(3 citation statements)

References 45 publications

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“…Forgerini et al [ 58 ] reported variants in the CYP2C9 gene, as the *2 and *3 alleles are responsible for the slow metabolism of NSAIDs, which increases the risk of gastrointestinal bleeding. Zhou et al [ 59 ] reported pronounced regional differences in the distribution of the CYP2C9*2 and *3 alleles, underscoring the importance of genetic variability in the CYP2C9 gene for the efficacy and safety of drugs on a global scale.…”

Section: Discussionmentioning

confidence: 99%

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

Yamate,

Ishiguro,

Fukuda

et al. 2024

PLoS ONE

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Background Rebamipide has been widely co-prescribed with non-steroidal anti-inflammatory drugs (NSAIDs) in Japan for decades. This study aimed to evaluate the effectiveness of rebamipide in preventing upper gastrointestinal bleeding in new users of NSAIDs without risk factors of NSAID-induced ulcers other than age. Methods A nested case-control study was conducted using medical claims data of 1.66 million inhabitants of 17 municipalities participating in Japan’s Longevity Improvement & Fair Evidence study. The cohort entry (t0) corresponded to a new user of NSAIDs for osteoarthritis or low back pain. Patients with risk factors of NSAID-induced ulcers other than age were excluded. Cases were defined as patients who underwent gastroscopy for upper gastrointestinal bleeding (occurrence date was defined as index date). A maximum of 10 controls were selected from non-cases at the index date of each case by matching sex, age, follow-up time, and type and dosage of NSAIDs. Exposure to rebamipide was defined as prescription status from t0 to index date: Non-user (rebamipide was not co-prescribed during the follow-up period), Continuous-user (rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs), and Irregular-user (neither Non-user nor Continuous-user). Conditional logistic regression analysis was conducted to estimate each category’s odds ratio compared to non-users. Findings Of 67,561 individuals who met the inclusion criteria, 215 cases and 1,516 controls were selected. Compared with that of Non-users, the odds ratios and 95% confidence interval were 0.65 (0.44–0.96) for Continuous-users and 2.57 (1.73–3.81) for Irregular-users. Conclusions Continuous co-prescription of rebamipide significantly reduced the risk of upper gastrointestinal bleeding in an Asian cohort of new users of NSAIDs with osteoarthritis or low back pain without risk factors other than age.

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Section: Discussionmentioning

confidence: 99%

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

Yamate,

Ishiguro,

Fukuda

et al. 2024

PLoS ONE

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“…In the case of the patient under investigation, ibuprofen was administered at a dosage of 600 mg, resulting in a total daily dose of 1200 mg, which is equal to the established Defned Daily Dose (DDD) for ibuprofen as designated by the World Health Organization [27]. Recent research conducted by Forgerini et al has demonstrated an increased risk of upper GI bleeding in individuals who carry the CYP2C9 * 3 allele and are taking more than 0.5 DDDs of NSAIDs [28]. Considering that our patient was a carrier of the CYP2C9 * 3 allele and utilized ibuprofen at a dose more than 0.5 DDD, it indicates an augmented vulnerability to upper GI bleeding at administrated dosage.…”

Section: Discussionmentioning

confidence: 99%

Association of CYP2C9∗3 and CYP2C8∗3 Non-Functional Alleles with Ibuprofen-Induced Upper Gastrointestinal Toxicity in a Saudi Patient

Bagher

2023

Case Reports in Medicine

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Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used to alleviate pain and inflammation. Although it is generally considered safe, common adverse drug reactions of ibuprofen include stomach pain, nausea, and heartburn. It can also cause gastrointestinal (GI) bleeding, especially in individuals with a history of GI ulcers or bleeding disorders. Ibuprofen is predominantly metabolized by the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C8. Individuals carrying the CYP2C9∗3 or CYP2C8∗3 non-functional alleles have reduced enzyme activities resulting in elevated ibuprofen plasma concentrations and half-life. We presented a case of a 31-year-old Saudi female patient with a history of rheumatoid arthritis (RA) who had taken ibuprofen at 600 mg twice daily for eight weeks. The patient presented to the emergency department with symptoms including nausea, vomiting, severe abdominal pain, and black tarry stools. An emergency esophagogastroduodenoscopy was performed on the patient, which revealed a deep bleeding ulcer measuring 1 × 1 cm in the antrum of the stomach. Laboratory investigations indicated anemia (hemoglobin: 7.21 g/dL and hematocrit: 22.40 g/dl). The patient received intravenous proton pump inhibitors and a packed red blood cell transfusion. Genetic analysis revealed that the patient was a carrier of CYP2C9∗3 and CYP2C8∗3 variant alleles, indicating that the patient is a poor metabolizer for both enzymes. The patient’s symptoms improved over the subsequent days, and she was discharged with instructions to avoid NSAIDs. This is the first reported Saudi patient homozygous for CYP2C9∗3 and CYP2C8∗3 variant alleles, which led to ibuprofen-induced upper GI toxicity. This case demonstrates the importance of contemplating CYP2C9 and CYP2C8 genetic variations when administrating NSAIDs like ibuprofen. Careful assessment of the risks and benefits of NSAID therapy in each patient and consideration of alternative pain management strategies must be conducted when appropriate.

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“…These variants are relatively rare in Iraq, but their impact on ARB therapy should not be overlooked. [ 7 ]…”

Section: Introductionmentioning

confidence: 99%

Clinical Pharmacogenetics of Angiotensin II Receptor Blockers in Iraq

Al-Hussaniy

Hassan

Oraibi³

et al. 2023

Journal of Pharmacy and Bioallied Sciences

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Background: Clinical pharmacogenetics is a rapidly growing field that focuses on the study of genetic variations and their impact on drug metabolism, efficacy, and safety. Angiotensin II receptor blockers (ARBs) are commonly used to treat hypertension in Iraq but not all patients respond equally to these drugs. Aim: This article aims to review the current evidence on the clinical pharmacogenetics of ARBs in Iraq and its implications for personalized medicine. Materials and Methods: We conducted a literature review of studies on the genetic variations that affect the response to ARBs in Iraq. We also reviewed the prevalence of these genetic variants in the Iraqi population and discussed the potential clinical implications for personalized medicine. Results: The most studied genetic variations associated with ARB response in Iraq are the angiotensin-converting enzyme gene insertion/deletion polymorphism and the angiotensin II type 1 receptor gene A1166C polymorphism. The angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with variability in response to ARBs, while the angiotensin II type 1 receptor A1166C polymorphism is associated with an increased risk of cardiovascular events in patients treated with ARBs. The prevalence of these genetic variants in the Iraqi population varies widely depending on the region and ethnic group. Conclusion: The clinical pharmacogenetics of ARBs in Iraq suggests that pharmacogenetic testing could improve the selection and dosing of ARBs in Iraqi patients, leading to better patient outcomes and cost-effective healthcare.

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The role of CYP2C92, CYP2C93 and VKORC1-1639 variants on the susceptibility of upper gastrointestinal bleeding: A full case-control study

Cited by 5 publications

References 45 publications

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

Association of CYP2C9∗3 and CYP2C8∗3 Non-Functional Alleles with Ibuprofen-Induced Upper Gastrointestinal Toxicity in a Saudi Patient

Clinical Pharmacogenetics of Angiotensin II Receptor Blockers in Iraq

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