Nuspojave lijekova supstrata metaboličkog enzima citokroma P450 CYP2C9 i transportnog P-glikoproteina

Autor: Macolić Šarinić, Viola
Přispěvatelé: Božina, Nada, dostupno, nije
Jazyk: chorvatština
Rok vydání: 2023
Předmět:
Popis: Polimorfni metabolički enzimi i transportni proteini mogu značajno modulirati farmakokinetske parametre lijekova i biti razlogom nastanku nuspojava tipa A. Stoga je cilj ovog istraživanja bio ispitati nuspojave lijekova supstrata metaboličkog enzima citokroma P450 CYP2C9 i transportnog P-glikoproteina (Pgp). Na temelju retrospektivno i prospektivno sakupljenih podataka o nuspojavama lijekova supstrata CYP2C9 i Pgp procijenili smo i ulogu polimorfizama u nastanku ozbiljnih nuspojava. Iz Nacionalne baze analizirane su sve prijave nuspojava na lijekove iz razdoblja 2005. – 2011. godine. Prijave koje su sadržavale lijekove supstrate CYP2C9, CYP2C9 i Pgp, odnosno lijekove koji su supstrati transportnog proteina Pgp uzete su za analizu ako su lijekovi čiji je klirens preko navedenog enzima veći od 10%, odnosno u razmatranje su uzeti i oni čiji je klirens putem CYP2C9 između 5 i 10%, a radi se o lijekovima koji se često koriste u kombinaciji s drugim lijekovima istovremeno kao što je to primjer kod acetilsalicilne kiseline. Iz baze obrađenih prijava nuspojava odabrana je skupina od 158 ispitanika s ozbiljnim nuspojavama na lijekove supstrate metaboličkog enzima CYP2C9. Birani su bolesnici koji su razvili nuspojave na lijekove koji se najvećim dijelom metaboliziraju putem enzima CYP2C9. To su prvenstveno bili antikoagulansi kumarinskog tipa, u našoj populaciji varfarin (n=30 ispitanika), nesteroidni protuupalni lijekovi ibuprofen, indometacin, diklofenak, piroksikam (n=32), antiepileptici fenitoin, fenobarbiton i valproična kiselina (n=44), fluvastatin (n=46), te oralni antidijabetici gliburid i glibenklamid (n=6). Skupini ispitanika s nuspojavama pridružena je skupina ispitanika bez nuspojava (n=155), koja je prema dobi spolu, bolestima i konkomitantnoj terapiji odgovarala skupini s nuspojavama. Provedena je genotipizacija CYP2C9*2*3 te ABCB1 2677G>T/A, 3435C>T. Analizom Nacionalne baze za nuspojave lijekova (HALMED), te provedbom farmakogenetičkih analiza utvrđeno je: • da se nuspojave na lijekove (bez cjepiva) u više od 60% pojavljuju u žena, što je također pokazano za lijekove supstrate CYP2C9, supstrate CYP2C9 &Pgp, te supstrate Pgp • 60% svih prijavljenih nuspojava u bazi i nuspojava za lijekove supstrate prijavljene su za odrasle osobe (od 17 do 69 godina starosti) • 8% lijekova u bazi su supstrati CYP2C9, CYP2C9&Pgp ili samo transportnog proteina Pgp, a na njih se odnosi 69% svih prijava • Nuspojave iz cijele grupe lijekova supstrata CYP2C9 imaju statistički značajno više ozbiljnih nuspojava u odnosu na ostale prijave u bazi (p
Polymorphic metabolic enzymes and transport proteins can significantly modulate the pharmacokinetic parameters of medicinal products and therefore be a reason for the appearance of type A adverse reactions. The objective of this study was to test the adverse reactions to medicinal product substrates of the metabolic enzyme cytochrome P450 CYP2C9 and the transport P-glycoprotein (Pgp). Based on the retrospective and current collection of data on adverse drug reactions of the substrates CYP2C9 and Pgp, the role of polymorphism in the appearance of adverse reactions was estimated. All adverse reactions reported to the National database in the period 2005–2011 were analysed. Reports pertaining to drug substrates CYP2C9, CYP2C9 and Pgp, i.e. drugs with a substrate of the transport protein Pgp, were analysed if the drugs had a clearance via the said enzyme of greater than 10%, or if the clearance via CYP2C9 was between 5 and 10%, and there are drugs commonly used in combination with other drugs simultaneous, as is the case, for example, with acetylsalicylic acid. A group of 158 subjects with serious adverse reactions to drugs with a substrate of the metabolic enzyme CYP2C9 were selected from the adverse reactions database. The selected subjects experienced adverse reactions to drugs that were, for the most part, metabolised via the enzyme CYP2C9. These were primarily anticoagulants of the coumarin type, i.e. warfarin (n=30 subjects), nonsteroidal anti-inflammatory drugs ibuprofen, indomethacin, diclofenac, pyroxicam (n=32), anti-epileptics phenytoin, phenobarbitone and valproic acid (n=44), fluvastatin (n=46), and oral anti-diabetics glyburide and glibenclamide (n=6). In addition to the group of subjects with adverse reactions, a second group was selected of subjects without adverse reactions (n=155) and who corresponded to the adverse reaction group in terms of gender, diseases and concomitant therapy. Genotypisation of CYP2C9*2*3 and ABCB1 2677G>T/A, 3435C>T was conducted. An analysis of the National Adverse Reactions Database (kept by HALMED), and subsequent pharmacogenetic analysis established the following: • Adverse reactions to drugs (excluding vaccines) appear in women in more than 60% of cases, which has also been shown for drugs with the substrate CYP2C9, substrate CYP2C9 &Pgp, and substrate Pgp. • 60% of all reported adverse reactions in the database and adverse reactions to drug substrates were reported for adults (aged 17 to 69 years). • 8% of all drugs are based on the substrates CYP2C9, CYP2C9&Pgp or only the transport protein Pgp, while 69% of all reaction reports pertain to these drugs. • Adverse reactions from the entire group of drug substrates CYP2C9 have a statistically significant higher incidence of serious adverse reactions in comparison to other reports in the database (p
Databáze: OpenAIRE
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