Michaelis-Menten kinetics phenytoin

Unfortunately, the elimination of some drugs does not follow first-order kinetics. For example, the primary pathway of phenytoin elimination entails initial metabolism to form 5-(parahydroxyphenyl)-5-phenylhydantoin (p-HPPH), followed by glucuronide conjugation (Figure 2.8). The metabolism of this drug is not first order but follows Michaelis-Menten kinetics because the microsomal enzyme system that forms p-HPPH is partially saturated at phenytoin... 

FIGURE 2.8 Metabolism of phenytoin to form p-HPPH and p-HPPH glucuronide. The first step in this enzymatic reaction sequence is rate limiting and follows Michaelis-Menten kinetics, showing progressive saturation as plasma concentrations rise within the range that is required for anticonvulsant therapy to be effective. 

Since phenytoin is eliminated by Michaelis-Menten kinetics. Equation 2.6 applies ... 

Yokochi K, Yokochi A, Giiba K, Ishizaki T. Flienytoin-allopmnol intemction Michaelis-Menten kinetic parametem of phenytoin with and without allopurinol in a child with Lesch-Nyhan syndr ne. TherDrugMornt (1982) 4,353-7. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

Several drugs, including salicylate (in overdose), alcohol, and possibly some hydrazines and other drugs which are metabolised by acetylation, have saturable elimination kinetics, but the only significant clinical example is phenytoin. With this drug, capacity-limited elimination is complicated further by its low therapeutic index. A 50% increase in the dose of phenytoin can result in a 600% increase in the steady-state blood concentration, and thus expose the patient to potential toxicity. Capacity-limited pathways of elimination lead to plasma concentrations of drugs which can be described by a form of the Michaelis-Menten equation. In such cases, the plasma concentration at steady state is given by... 

AH of the equations previously described for predicting dose or concentration assume linear kinetic systems they are therefore not adaptable to treatment with drugs that display nonlinear kinetics. Using a linearized Michaelis-Menten equation, methods for predicting phenytoin dose and concentration have been developed and apphed to individual drug dosing regimens. 

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