INFLUENCE OF POTENTIAL GENE POLYMORPHISMS
ON PROPOFOL DOSAGE REGIMEN IN PATIENTS
UNDERGOING ABDOMINAL HYSTERECTOMY
Ivanov E, Sterjev Z, Budic I, Nojkov J, Karadzova D, Sivevski A
*Corresponding Author: Emilija Ivanov, Prim. M.Med., University Clinic for Gynecology and Obstetrics,
University “Ss Cyril and Methodius” Medical Faculty, Mother Theresa, Skopje, Republic of North
Macedonia. Tel./Fax: +389-(0)-23-228-440. E-mail: emilijaivanov@gmail.com
page: 41
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INTRODUCTION
The inter individual variability in response to a drug
is quite common and depends on clinical, environmental,
social and genetic factors [1]. Pharmacogenetics generally
determines variations of a single gene or several genes
that influence drug response, while pharmacogenomics
indicates drug response variations due to multi gene variations
that are encompassed within the whole genome. As
a result, gene mutations can potentially affect the response
to drugs, which is a common biological phenomenon [2].
Propofol (2,6-diisopropylphenol) is the most common
intravenous anesthetic used in modern medicine.
Induction in general anesthesia with propofol occurs due
to inhibition of γ-aminobutyric acid type A (GABAA)
receptor-mediated neurotransmission [3]. Its significant
and prominent use in clinical practice is mainly based on
its rapid action, relatively low toxicity, prompt recovery
after anesthesia and minimal side effects, even after a long
period of anesthesia.
The main metabolic pathway of propofol includes
oxidation by the cytochrome P450 2B6 isozyme (CYP2B6),
and to a lesser extent cytochrome P450 2C9
isozyme, followed by phase II metabolism by UDP-glucuronosulfotransferase
1A9 (UGT1A9). The cytochrome
P450 enzymes (CYP2B6 and CYP2C9) are responsible
for the formation of a hydroxyl derivative of propofol- 4-hydroxypropophol, which can further be transformed
into 4-hydroxypropophol-1-ObD-glucuronide (Q1G) and
4-hydroxypropophol-4-ObD-glucuronide (Q4G). About
70.0 to 90.0% of propofol is eliminated by urine in the
form of the glucuronide metabolite [3,4].
It is postulated that individual differences in genetic
factors [polymorphism of single nucleotide polymorphisms
(SNPs)] in the genes encoding these enzymes can
be responsible for susceptibility to propofol effects [5,6].
The polymorphism of the CYP2B6 gene (c.516G>T) decreases
the metabolism of propofol and individuals with
this polymorphism have been associated with high plasma
concentration of propofol [7]. Mutations in genes involved
in the molecular targets and molecular binding sites of
propofol may also be associated with propofol susceptibility,
including the dominant variations (rs2279020) in
GABAA receptor α1 subunit GABRA1 gene [8]. The mutation
in P-glycoprotein (P-gp) transporter also known as
multi drug resistance ABC transporter 1 (ABCB1/MDR1),
SNP c.1236 C>T (rs1045642), is partly the reason for single
differences in the anesthetic effects [9]. Patients who
are homozygous for the T allele have two to three times less
expression of P-gp. This change may result in increased intestinal
absorption, decreased renal clearance, or increased
brain concentration of various toxic substances [10,11].
This was confirmed in a study of Zhang et al. [9], who
found that propofol/remifentanil anesthetic effect following
pediatric tonsillectomy in patients with the CC genotype
of MDR1 c.1236C>T (rs1045642) polymorphism
was stronger than in those carrying the CT+TT genotype.
Li et al. [12] found that the ABCB1 (C3435T), did not
correlate with efficacy of sufentanil/propofol combination
in patients undergoing gynecologic laparoscopic surgery.
Our study aimed to investigate the influence of different
SNPs in selected genes on propofol therapeutic
outcomes in the patients undergoing abdominal hysterectomy.
For that reason, we examined the distribution of the
CYP2B6 (rs3745274), GABRA1 (rs2279020) and ABCB1
(rs1045642) gene polymorphisms in our patient group. In
this study, we also evaluated the possible influence of these
polymorphisms on anesthesia induction time, administered
doses of propofol, wake time after surgery and the most
common side effects from anesthesia with propofol.
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