Thiotepa

In this article, we will discuss Thiotepa (Mechanism of Action). So, let’s get started.

Mechanism of Action

Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to the nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethyleneimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principle bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates alkylated guanines.

Pharmacokinetics

Absorption

Thiotepa reached maximal concentrations close to the end infusion following an intravenous infusion.

Distribution

The binding of thiotepa to plasma proteins is approximately 10% to 20%. The mean volume of distribution (% coefficient of variation) of thiotepa was 30 L/m² (44%) or 1.2 L/kg (47%) following a single intravenous infusion of Thiotepa at a dose of 5 mg/kg over 3 hours in pediatric population. In adults administered intravenous thiotepa between 20 mg to 250 mg/m² as an intravenous bolus or infusion up to 4 hours, the mean volume of distribution of thiotepa ranged from 1.0 L/kg (30%) to 1.9 L/kg (17%).

Elimination

Following a single intravenous infusion over 3 hours of Thiotepa at a dose of 5 mg/kg in pediatric population, the estimated mean (% coefficient of variation) clearance of thiotepa was 0.58 L/hr/kg (60%) or 13.8 L/hr/m² (52%). The mean terminal elimination half-life was 1.7 hours (64%) for thiotepa and 4 hours (29%) for its major active metabolite, N,N’,N”­ triethylenephosphoramide (TEPA) in pediatric population. In adults administered intravenous thiotepa between 20 mg to 250 mg/m² as an intravenous bolus or infusion up to 4 hours, the mean thiotepa clearance ranged from 14.6 L/hr/m² (23%) to 27.9 L/hr/m² (69%). In adult population, the mean terminal elimination half-life ranged from 1.4 hours (7%) to 3.7 hours (14%) for thiotepa and from 4.9 hours to 17.6 hours (20%) for TEPA.

Metabolism

Thiotepa undergoes hepatic metabolism. In vitro data suggests that CYP3A4 and CYP2B6 may be responsible for the metabolism of thiotepa to TEPA, a major active metabolite.

Excretion

In adult and pediatric patients, urinary excretion of thiotepa accounted for less than 2% of the dose and TEPA accounted for 11% or less of the dose.

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