Ocsaar and CYP2C9 Ploymorphism, Is There a Connection Between Pharmacokinetics, Pharmacodynamics and Pharmacogenetics?
Information source: Assaf-Harofeh Medical Center
Information obtained from ClinicalTrials.gov on October 19, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypertension
Intervention: losartan (Drug); valsartan (Drug)
Phase: N/A
Status: Not yet recruiting
Sponsored by: Assaf-Harofeh Medical Center Official(s) and/or principal investigator(s):
Ronit Koren Peleg, MD, Principal Investigator, Affiliation: Department of Internal Medicine A , Research & Development unit Assaf Harofeh Medical Center, Zerifin, affiliated to Sackler School of Medicine, Tel Aviv, Israel
Overall contact:
Ronit Koren Peleg, MD, Phone: 972-524-535024, Email: ronitkoren@gmail.com
Summary
Most Angiotensin receptor blocker's (ARBs) are metabolized by cytochrome P4502C9 (CYP2C9),
one of the major isoforms of the cytochrome P450 in human liver microsome. The purpose of
this study is to evaluate whether CYP2C9 polymorphism has a significant clinical influence
on the blood pressure lowering effect of losartan and valsartan. Weather there is a genetic
importance in choosing the right ARB for the right patient.
Clinical Details
Official title: Ocsaar and CYP2C9 Ploymorphism, Is There a Connection Between Pharmacokinetics, Pharmacodynamics and Pharmacogenetics?
Study design: Other, Open Label, Active Control, Single Group Assignment, Pharmacokinetics/Dynamics Study
Primary outcome: Blood pressure lowering effect of losartan and valsartan in patients with different CYP2C9 allels
Secondary outcome: losartan/E-3174 ratio in different allelic groups of CYP2C9
Detailed description:
Losartan, the first angiotentsin II receptor blocker (ARB), is known to reduce blood
pressure (BP). The LIFE study, Cardiovascular Morbidity and Mortality in the Losartan
Intervention for Endpoint Reduction, showed that losartan prevented more cardiovascular
morbidity and mortality than the ß receptor blocker atenolol. This effect was independent of
its BP lowering effect. Left ventricular hypertrophy (LVH) is known to be a cardinal
manifestation of BP and an independent risk factor for cardiovascular complications. In the
patient subgroup of isolated systolic hypertension, losartan was found to reduce
cardiovascular and all cause mortality and to reverse LVH.
ARBs are used for the treatment of hypertension, alone or in combination with other
antihypertensive drugs, such as calcium channel blockers, diuretics or angiotensin I
converting enzyme (ACE) inhibitors. ACE inhibitors and ARBs may also have an important role
in the prevention of type II diabetes and should be considered first line agents in
hypertensive patients with impaired fasting glucose or metabolic syndrome.
Most ARBs are metabolized by cytochrome P4502C9 (CYP2C9), one of the major isoforms of the
cytochrome P450 in human liver microsome. It converts losartan to its pharmacologically
active metabolite EXP-3174 (E-3174). Other ARBs such as telmisartan and olmesartan are
innate to CYP2C9, whereas candesartan and valsartan are metabolized by it to
pharmacologically inactive metabolites. Maximal concentration of the drug is reached two
hours post administration. Fourteen percent of the orally administered medication is
converted to E-3174, which is 10 to 40 fold more potent than losartan. The pharmacokinetics
of losartan and E-3174 are linear, dose dependent and do not change after repetitive
administration. The CYP2C9 gene has three main polymorphic variations caused by single
nucleotide polymorphism; the most common allele is CYP2C9*1 (Arg144 Ile359), and the two
less common CYP2C9*2 (Cys 144Ile359) and CYP2CP*3 (Arg144Leu359) that code for an enzyme
with decreased activity. The oxidation of losartan is decreased 2,3 and 40 fold in
individuals genotyped as CYP2C9*1*3, CYP2C9*2*3 and CYP2C9*3*3 compared to individuals
genotyped as CYP2C9*1*1. CYP2C9*3 was found to influence losartan's metabolism more than does
CYP2C9*2.
The distribution of CYP2C9 allelic variants within different ethnic groups varies. In
Caucasians the allele frequencies of CYP2C9*1, CYP2C9*2 and CYP2C9*3 have been reported to
be 0. 79-0. 86, 0. 08-0. 135 and 0. 03-0. 085 respectively, whereas very low frequency of the
alleles CYP2C9*2 and CYP2C9*3 have been reported in Asian populations (0 and 0. 02-0. 05
respectively). Ashkenazi Jews were found to have similar prevalence of allele polymorphism
as North American Caucasian population (the CYP2C9*1, *2, *3 allele frequencies were 0. 772,
0. 140 and 0. 086, respectively). Nakai K et al. evaluated the population prevalence of the
different alleles in four different ethnic groups in the Israeli population: Ashkenazi,
Moroccan, Libyan and Yemenite Jews. They found that in the Ashkenazi population, the
prevalence of CYP2C9*1, CYP2C9*2 and CYP2C9*3 variants was 0. 83, 0. 17 and 0. 15 respectively,
in the Yemenite population 0. 89, 0. 1 and 0. 15 respectively, in the Moroccan population 0. 81,
0. 19 and 0. 23 respectively and in the Libyan population 0. 69, 0. 27 and 0. 31 respectively.
Many drugs have been found to be substrates for CYP2C9, including fluoxetine, losartan,
phenytoin, tolbutamide, torsemide, warfarin, and numerous NSAIDs. CYP2C9 activity is
inducible by rifampicin and possibly also by carbamazepine, ethanol and phenobarbitone.
Several drugs have been reported to inhibit CYP2C9 activity in vivo or in vitro, for
example: fluconazole, amiodarone, trimethoprim, fluvastatin, cimetidine and chloramphenicol.
An in vitro study demonstrated that the clearance of losartan was reduced significantly in
human liver microsomes obtained from CYP2C9*3*3 and CYP2C9*2*2 homozygous individuals, and
from CYP2C9*3*1 heterozygous individuals but not from CYP2C9*2*1 individuals. In this study,
no clear conclusion could be made regarding the CYP2C9*2*3 genotype. In another study, no
influence of the CYP2C9 polymorphism on the pharmacokinetics of losartan or E-3174 was found
after a single oral dose of 50 mg losartan.
Irbesartan undergoes metabolism through the CYP2C9 to an inactive metabolite. Hallberg P et
al. randomly assigned 115 hypertensive patients to be treated with atenolol or irbesartan.
They found that the CYP2C9 genotype predicted the BP response to irbesartan and had no
influence on the effect of atenolol.
Purpose:
The purpose of this study is to evaluate whether CYP2C9 polymorphism has a significant
clinical influence on the BP lowering effect of losartan and valsartan. Weather there is a
genetic importance in choosing the right ARB for the right patient.
Methods
Patients:
A screening period will be conducted in which hypertensive patients aged 18 years and over,
will undergo a genetic evaluation for CYP2C9 polymorphism.
Patients will sign a written informed consent before their inclusion in the study. No other
change in patients' medication regimen will be made.
Study design:
The study will be a prospective non randomized trial. All patients fulfilling the inclusion
and exclusion criteria will be treated with losartan 50 mg once daily for one month. After a
wash out period of one week losartan treatment will be replaced with valsartan 160 mg once
daily. Patients will be evaluated at baseline and following losartan and valsartan
treatment. Patients will undergo a 24 hour ambulatory BP monitoring at baseline, one months
following losartan treatment and one month following valsartan treatment. Creatinine and
Potassium levels will be measeured at baseline and one week following each drug
administration, blood sample will be collected to measure the losartan/ E-3174 ration.
Genetic evaluation:
Polymerase chain reaction amplification will be preformed with the use of specific primers.
Genotyping of the polymorphic CYP2C9 genes will be made using real time PCR (RT PCR)
technology with Roche light cycler. The procedure is made in a closed system which decreases
the chance for contamination.
Losartan and E-3174 Analysis:
The losartan and e-3174 assays will be performed using a reversed phase high performance
liquid chromatography (HPLC) method. Hewlett Packard HP-1090 Series II will be used.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- The study will include 30 patients with the 3 most prevalent alleles of CYP2C9 *1,
*2 and*3, 10 patients of each group.
Exclusion Criteria:
- Patients treated with losartan or valsartan prior to their enrollment to the study,
- Patients with BP below 140 systolic or 90 diastolic in an ambulatory 24 hours BP
monitoring, acute coronary syndrome during the 6 months previous to the study,
- Renal failure with creatinin levels above 1. 5 mg/dL, hyperkalemia (K > 5 mg/dL),
- Hematologic or solid malignancies or pregnancy.
- Patients will also be excluded from the study if they are known to use one of the
drugs inducing or inhibiting the CYP2C9, such as
- rifampicin carbamazepine,
- ethanol,
- phenobarbitone,
- fluconazole,
- amiodarone,
- trimethoprim,
- fluvastatin,
- cimetidine
- chloramphenicol.
Locations and Contacts
Ronit Koren Peleg, MD, Phone: 972-524-535024, Email: ronitkoren@gmail.com Additional Information
Starting date: September 2008
Last updated: August 11, 2008
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