Abubakar, Murtala Bello
(2017)
The impact of CYP3A4 and CYP3A5 polymorphisms on anastrozole's pharmacokinetics and pharmacodynamics in post-menopausal breast cancer patients.
PhD thesis, Universiti Sains Malaysia.
Abstract
Breast cancer is the second most frequent cancer among all cancer types and is by far
the commonest cancer in women. Anastrozole is one of the first line drugs of choice
in the treatment of breast cancer and is believed to be superior to tamoxifen.
However, a significant proportion of patients treated with anastrozole experienced
recurrences of breast cancer or developed severe adverse drug reactions. This interpatient
variability is attributed to a number of factors such as genetic variations.
Anastrozole is predominantly metabolized by CYP3A4 and CYP3A5 enzymes. The
objective of this study was to determine the impact of CYP3A4 and CYP3A5 genetic
polymorphisms on anastrozole’s pharmacokinetics and pharmacodynamics in postmenopausal
breast cancer women. A total of 94 postmenopausal breast cancer
women were recruited for this study. Patients’ socio-demographic data and clinical
variables were recorded and blood samples were collected for DNA acquisition,
hormonal and anastrozole serum levels. Genotyping of CYP3A4*18A and CYP3A5*3
was performed using the conventional polymerase chain reaction-restriction
fragment length polymorphism (PCR-RFLP), while that of CYP3A4*4,
CYP3A4*18B and CYP3A4*22 was carried out by a novel multiplex PCR-RFLP
method. Serum anastrozole concentration was determined by an ultra-high
performance liquid chromatography (UHPLC) method using a simple solid-phase
extraction procedure. Our study reported that CYP3A4*18B G>A has a high
frequency (0.48) among Malaysians and that CYP3A4*18A T>C and CYP3A5*3A>G occur in low (0.03) and high (0.64) frequencies respectively among
Malaysians. No variant alleles of CYP3A4*4 and CYP3A4*22 were detected among
all the subjects. Patients homozygous for CYP3A4*18B G>A and CYP3A5*3 A>G
had lower and higher anastrozole serum levels respectively compared to those having
the respective wild types or heterozygous variants. The multiplex PCR-RFLP method
for the simultaneous detection of CYP3A4*4 A>G, CYP3A4*18B G>A and
CYP3A4*22 C>T, was applied in genotyping of all the subjects. The newly
developed UHPLC method demonstrated a good linearity over concentration ranges
of 20 – 1600 ng/mL. The mean recovery for anastrozole was 88.17% with a limit of
quantitation of 20 ng/ml. Variables such as patients’ age and time since
commencement of anastrozole therapy were associated with higher risk of
developing vasomotor symptoms and mood disturbances and/or vaginal
dryness/dyspareunia respectively. No significant association was established between
CYP3A4 and CYP3A5 genetic polymorphisms and anastrozole’s pharmacodynamics.
The detected CYP3A4*18B G>A and CYP3A5*3 A>G alleles may serve as an
important biomarkers of altered anastrozole metabolism in breast cancer patients
receiving anastrozole in future.
Actions (login required)
 |
View Item |
