How long it would take for the effect of 1 tablet of methotrexate to be significantly reduced after the maximum effect has been achieved?

Question

Methotrexate is a drug used in anticancer therapy. It acts as a competitive inhibitor of dihydrofolate reductase(DHFR), which ultimately leads to reduced cell replication.

DHFR catalyses the reduction of dihydrofolicacid(DHF) to tetrahydrofolicacid.The cellular

concentration of DHF can be assumed to be [DHF] = 3.0 μM, while the Michaelis Menten constant(KM)of the uninhibited conversion of DHF by the homo sapiens DHFR is 1.9 μM.

Methotrexate is available as a targeted oral formulation containing 2.5 mg methotrexate per dose(per tablet). The bioavailability of methotrexate is 80%, it has a half life (t1/2) of 6.5 hours and an IC50of 100 μM.

Using the data above, calculate how long it would take for the effect of 1 tablet of methotrexate to be significantly reduced after the maximum effect has been achieved (i.e. after the full bioavailable amount is present in the circulation).

Assume that for a significant reduction of the effect, the reaction rate of DHFR has to increase to half the maximum reaction (Vmax) of the catalytic reaction. Furthermore, assume the total volume of the tissue to which the drug has been distributed to be 0.1 L.

Answer 1

It will take 5 (T1/2) to remove over 95% of Methotrexate Total hours= 5 X 6.5 = 32.5 hours