Fate of Zytiga in the Human Body

What is the fate of Zytiga when it enters the human body ? How is it processed by the human enzymes ? This all depends on metabolism and the drug metabolism of Zytiga has been thoroughly investigated. This takes place as part of the overall ADME process involving Absorption, Distribution, Metabolism, and Excretion.

For Zytiga (Abiraterone Acetate) only about 5 % is absorbed by the intestine in an unfed state. This means that for a 1000 mg (4 tablet) dose only about 50 mg is being absorbed. The absorption of Zytiga greatly increases when taken with food and a single tablet dose of 250 mg taken shortly after eating results in the absorption of 60 mg of drug which is higher than the full dose taken on an empty stomach.

Absorption of Zytiga

Zytiga as Abiraterone Acetate is taken orally and enters the stomach where it is solubalised by bile acids which are released after eating a meal. The Zytiga tablets disintegrate in the stomach and the released Abiraterone Acetate passes along the small intestine where it is absorbed across the intestinal wall and enters the bloodstream.

Cleavage by Plasma Esterases

The intestinal bloodstream passes through the liver where Abiraterone Acetate escapes first pass metabolism and enters the bloodstream to the rest of the body. In the bloodstream plasma esterases cleave Abiraterone Acetate which is an ester to liberate free Abiraterone.

Binding of Abiraterone to CYP17

The free Abiraterone is then delivered by the bloodstream to the organs of the body including the prostate, the gonads, and the adrenal glands. Here Abiraterone binds tightly to the enzyme CYP17 preventing it from working. This enzyme CYP17 is responsible for making all of the androgens in the human body and so inhibiting CYP17 with Abiraterone causes all androgen production to stop and testosterone levels reduce to zero. This starves the prostate tumours of testosterone and they cease multiplying and start regressing.

Metabolism of Abiraterone by CYP3A4

CYP3A4 makes the inactive metabolite Abiraterone N-oxide. With its pyridyl nitrogen oxidised to the N-oxide Abiraterone is unable to block CYP17 and is rendered inactive.

Metabolsim of Abiraterone N-oxide by SULT2A1

The steroid sulfatase enzyme SULT2A1 puts a sulfate group onto the 3-hydroxy group of Abiraterone N-oxide to make the water soluble Abiraterone N-Oxide Sulfate which is excreted in the urine. About 4 % of Zytiga ends up in this way as the fully metabolised Abiraterone N-oxide Sulfate.

So the Zytiga that enters the human body is processed in a very precise way that allows Zytiga sufficient time to work and yet clears the drug safely from the system.

Molecular Structur of Abiraterone