Inhibition

Auto inhibition is a phenomenon where a drug inhibits the activity of enzymes that are responsible for its own metabolism. This can lead to a decrease in the rate at which the drug is metabolized over time, resulting in an increase in its plasma concentration and potentially enhancing its therapeutic effects or increasing the risk of toxicity.

Inhibition can be computed by two ways on Teoreler - Reversible and Time-dependent.

Reversible

Reversible inhibition assumes that the inhibitor binds to the enzyme in a reversible manner, meaning that the binding can be easily reversed when the inhibitor is removed. This type of inhibition typically results in a temporary decrease in enzyme activity, which can be restored once the inhibitor is no longer present.

Reversible inhibition (competitive inhibition) ¹^,, is given as follows:

Inh_{enz} = 1 + \frac{C_{drug}}{K_i}

[ 1 ]

where, Inh_enz is the fold inhibition of the enzyme, C_drug is the concentration of the drug in the liver or gut at a given time, and K_i is the inhibition constant and can be calculated using the equation below:

For competitive inhibition,

K_i = \frac{I_{50}}{1 + \left(\frac{S}{K_m}\right)}

[ 2 ]

For noncompetitive and uncompetitive inhibition,

K_i = I_{50}

[ 3 ]

where, I₅₀ is the concentration of inhibitor that causes 50% inhibition, S is the substrate concentration, and K_m is the Michaelis-Menten constant for the substrate.

Time-dependent

Time-dependent inhibition (TDI) involves the formation of a stable complex between the inhibitor and the enzyme, leading to a prolonged decrease in enzyme activity. This type of inhibition often results in a more sustained reduction in enzyme function, as the inhibitor remains bound to the enzyme for an extended period, even after the inhibitor concentration decreases.

In an TDI model², rate of enzyme inhibition is computed as follows:

\frac{dInh_{enz}}{dt} = k_{deg} \times \left(1 - Inh_{enz}\right) - \left(\frac{k_{inact} \times C_{drug}}{K_i}\right) \times Inh_{enz}

[ 4 ]

where, dInh_enz/dt is the change in fold inhibition of the enzyme over time, k_deg is the degradation rate constant of the enzyme, k_inact is the maximal enzyme inactivation rate constant.

References

Yung-Chi C, Prusoff WH. Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochemical Pharmacology. 1973;22(23):3099-108. https://doi.org/10.1016/0006-2952(73)90196-2
Peters, S.A. Evaluation of Drug–Drug Interaction Risk with PBPK Models. Physiologically‐Based Pharmacokinetic (PBPK) Modelling and Simulations; 2012. p.183-207. https://doi.org/10.1002/9781118140291.ch9

< Induction

Elimination >