Effect of Genetic Polymorphisms of UGT on the PKs of Indapamide in Egyptians

The aim of this works is to investigate the effect of genetic variation of UGT2B7 on human response to treatment with indapamide and its correlation with pharmacokinetic parameters in Egyptian subjects.

Indapamide is a thiazide-type diuretic commonly prescribed to treat mild to moderate hypertension. As it has fewer side effects in inducing metabolic derangements than other thiazide diuretics, indapamide is well accepted to be used as initial therapy to treat hypertension in patients with previous stroke or older people (over 80) or as an add-on treatment. However, severe hyponatremia and hypokalemia have been reported. Therefore, limiting the dose to that necessary to achieve maximal blood pressure reduction and improved cardiovascular outcomes is relevant. Although the major metabolites of indapamide have been identified, the pathways of cytochrome P450 (CYP450)-catalyzed indapamide biotransformation have not been fully elucidated. One recent report suggested that CYP2C19, CYP2C8, and CYP3A4 are involved in the metabolism. Recent advancement in the field of glucuronidation has identified a high degree of allelic diversity for human uridine diphosphate glucuronosyl transferases (UGTs).

As indapamide is glucuronidated by UGT enzymes, poly-morphisms in the genes encoding these drug-metabolizing enzymes could potentially influence its PK. Large inter-individual variability in the rate of glucuronidation of various drugs has been reported. The UGT2B7 enzyme is expressed in the liver and many extrahepatic tissues. Mutations in the UGT2B7 gene may therefore have pharmacological, toxicological, and physiological significance.

the investigators have little information on pharmacogenetics (PG) studies of indapamide. The effect of genetic variation on DMEs activity and the clinical impact on indapamide in particular are not fully understood.

The ultimate goal of personalized medicine is to identify specific genetic features with the differential risk of human diseases or the efficacy of certain therapeutic interventions . Mounting evidence has linked the genetic make-up to a significant portion of drug-induced toxicity. The primary focus of PG is DMEs activity.

The pharmacology of drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathway of elimination. In addition, ethnicity may account for the observed differences in both pharmacokinetics (PK) and pharmacodynamics of drugs, thus resulting in variability in response to drug therapy. Furthermore, genetic polymorphism is one of the most important factors that may contribute to the ethnic sensitivity of a drug in its metabolic pathways.

Single nucleotide polymorphism (SNP) is the most frequently observed mutation in all organisms. The cost for mapping of the genetic variance among thousands of SNPs could be extremely high. Recent advances in whole-genome sequencing (WGS) have led to burst of bioinformation and a significant knowledge base for investigating the genetic architecture of drug metabolisms and treatment efficacies.

Eligibility Criteria:
Inclusion Criteria:

* Subjects should be healthy adult volunteers with age between (18-45) with normal body weight.
* The volunteers will be asked to provide a complete medical history, and complete a physical examination, laboratory tests (hematology, clinical chemistry, urinalysis, serology (including hepatitis B surface antigen, anti-hepatitis C virus and antihuman immunodeficiency virus antibody)

Exclusion Criteria:

* Treatment with any known enzyme -inducing /inhibiting agent within 30 days prior to the start of the study and throughout the study.
* Subjects who have taken any medication less than two weeks of the trials starting date
* Susceptibility to allergic reaction to study drugs
* Any prior surgery of the gastrointestinal tract that may interfere with drug absorption
* Gastrointestinal diseases
* Renal diseases
* Pancreatic disease including diabetes
* Hepatic diseases
* Hematological diseases or pulmonary diseases
* Abnormal laboratory values
* Subject who have donated blood or who have been involved in multiple dosing study requiring a large volume of blood (more than 500 ml) to be drawn within 6 weeks preceding the start of the study.