A Comparison of Letrozole and Tamoxifen
Tamoxifen is marketed under the brand name Nolvadex®. It is
indicated in patients with breast cancer or anovulatory infertility. It has
been shown in studies that a five year course of treatment with tamoxifen
reduces the risk of the recurrence of breast cancer by 47%. It also reduces the
risk of death of patients with a hormone receptor positive breast cancer by 26%.
Letrozole is marketed under the brand name Femara®. It is used as an
adjuvant treatment of patients with invasive early hormone receptor positive
breast cancer and as first line treatment in patients with advanced breast
cancer that is hormone dependant. Letrozole is most commonly used in
postmenopausal patients. Femara has not been studied with regards to the
treatment of breast cancer in men.
Compartment Models in pharmacokinetics are used to describe the path
the drug takes in the body, which is split into different compartments.
The One-Compartment Model can be applied to Tamoxifen. A
One-Compartment model can be explained as the body acting like a single
continuous compartment for the absorption, distribution and elimination of the
drug. This means that the rates of absorption, metabolism and excretion can be
assumed to have a direct proportionality to the concentration of Tamoxifen in
Letrozole is considered to follow the Two-Compartment Model. This
type of model divides the body into two compartments – peripheral and central
compartments. The central compartment includes the tissues and the plasma where
the drug is absorbed and distributed immediately. The peripheral compartment on
the other hand consists of tissues where the drug is distributed to at a slower
A paper by S. Yuan has also been published testing the above model
given to Tamoxifen. The paper published the results that there was a
significant difference in the absorption and metabolism rates in the peripheral
and central compartments, the central compartment having much higher rates,
proving that the Pharmacokinetic Model of Tamoxifen is a One-Compartment Model.
Letrozole is known to have a mean absolute bioavailability of 99%.
This means that it is fully absorbed through the gastrointestinal tract at a
Tamoxifen is also rapidly absorbed, post-oral administration, to
reach its highest concentrations in serum after 4-7 hours.
ADD ONE COMPARTMENT AND TWO COMPARTMENT DIAGRAMS
An important part of clinical trials is determining the affinity of
the drug to blood proteins, most commonly albumin. Letrozole has a plasma
protein binding of around 60%, 55% of it to albumin. On the other hand,
Tamoxifen is more highly bound to proteins, being 99% bound to serum albumin.
This leads to a very high apparent volume of distribution (Vd) at steady state
(50 liters/kg) when compared to the low apparent volume of distribution at
steady state of Letrozole (2 liters/kg). This shows how, as mentioned before,
Tamoxifen follows a One-Compartment Model since there is a very high
distribution to the peripheral tissues with only a small amount of the
administered drug in the other compartments of the body. This type of
pharmacokinetic feature is common with highly lipophilic and basic drugs such
The major pathway by which Letrozole
is eliminated in the body is by the clearance of Carbinol. The metabolism of
Letrozole to Carbinol is known to be due to the action of two Cytochrome P450
isoenzymes in the liver. The action of Letrozole is aided when the drug
competitively binds to the heme group of the cytochrome P450 subunit of the
aromatase enzyme resulting in the inhibition of the enzyme, thus the reduction
of oestrogen synthesis in the tissues.
Other forms of metabolism of Letrozole, such as excretion by faecal
route via the formation of other metabolites, among others, is considered to
play only a minor role.
Tamoxifen, on the
other hand, is highly metabolised after administration. The major metabolite is
N-Desmethyl-Tamoxifen and is found in high plasma concentrations. The extensive
metabolism of Tamoxifen does not prove to be problematic as the metabolite also
has a similar pharmacologic activity to Tamoxifen. 4-Hydroxy-Tamoxifen is also a
metabolite of Tamoxifen found in the plasma. This metabolite is formed by the
action of Cytochrome P450 along with other enzymes. Compared to Tamoxifen, its
metabolites have a greater affinity for oestrogen receptors and also inhibit
the oestrogen-dependant cell proliferation at a greater strength. Thus, the
metabolism of Tamoxifen aids the drugs’ action even further.
was found present on the first day of testing where as N-Desmethyl-Tamoxifen
was measured in urine and bile up to 4 days after administration. Thus,
4-Hydroxy is considered to be a metabolite obtained via First Pass Effect.
Studies have been
conducted on both Letrozole and Tamoxifen to obtain results on how much of the
drug is excreted by the body and through which routes excretion is most common.
These studies involve the reaction of the coumpounds with radioactive 14-C
compounds involve the reaction of the co to be able to measure the percentages
of each. Table 1 below shows the information gathered among several
studies for both Tamoxifen and Letrozole:
Zero Order or First Order
Rate of Drug Metabolism
Extensive and Immediate
Activity of Metabolites
30-100x more potent than Tamoxifen
Renal Elimination was the Main Route.
Renal, Faecal and Biliary Excretion Mechanisms
88% of Drug in
– 75% Carbinol
– 6% Unchanged Letrozole
– 7% Other Metabolites
4% of Drug in