Does Phenytoin follow Pseudo Zero Order Elimination kinetics ?
The straightforward answer to the above question is NO . This misconception is prevalent because Phenytoin follows Zero order kinetics at toxic doses and first order kinetics at therapeutic doses.
To gain a better insight into this we need to understand what is Pseudo Zero order kinetics and elimination kinetics of Phenytoin separately.
Pseudo Zero Order Kinetics
In pharmacology, we have two major types of elimination –
- Zero order Kinetics: In which the amount of drug excretion is constant and it doesn’t depend upon the concentration of the drug.
- First order Kinetics: Rate of drug elimination is directly proportional to the drug concentration.
As per the rate law for the elimination of drug A :
R = K [ A ]x
where, R = Rate of elimination of drug A
K = Elimination constant
[A] = Plasma Concentration of drug A
x = Order of elimination
Zero Order Kinetics: x = 0
First Order Kinetics: x = 1
Now lets think of a scenario where a patient swallows a tablet. As soon as the tablet enters into the mucosa of gastrointestinal tract the tablet encounters moisture. Now at the instant of this reaction, there is a large amount of drug (in tablet form) relative to the amount of moisture. It is at this instant where the drug’s dissociation is limited by the amount of moisture. So a large amount of it is dissociated and forms suspension. It appears to us that the dissociation of the drug is independent of the its own concentration (which is a characteristic of zero order kinetics) but actually the whole reaction is a first order kinetic reaction(more the amount of drug more is its dissociation).
Hence a pseudo zero order kinetics is a type of elimination kinetics that appears to follow zero order kinetics but is actually a result of first order elimination with a large amount of the drug . In a zero order reaction the rate of the reaction is independent of the amount of the reactant whereas in a pseudo order reaction the rate of the reaction appears to be independent of the amount of the reactant(drug) but is actually dependent on the concentration of other reactant(moisture).
Phenytoin – Elimination Kinetics
Phenytoin follows Zero order kinetics at toxic doses and first order kinetics at therapeutic doses.
Phenytoin undergoes hydroxylation in liver to form hydroxy-phenytoin which is further converted to phenytoin catechol and then phenytoin-quinone which is eliminated into the urine. At therapeutic doses phenytoin is excreted via first order kinetics and at higher/toxic doses it undergoes zero order elimination due to the saturation of hepatic hydroxylation system.
