Phenytoin saturable metabolism

Metabolism/Excretion - Phenytoin is metabolized in the liver and excreted in the urine. The metabolism of phenytoin is capacity-limited and shows saturability. Elimination is exponential (first-order) at plasma concentrations less than 10 mcg/mL, and plasma half-life ranges from 6 to 24 hours. 

Drugs that are exhibit saturable metabolism (zero-order kinetics), when small interference with kinetics may lead to large alteration of plasma concentration, e.g. phenytoin, theophylline... 

Drugs that show saturable metabolism within the therapeutic range include phenytoin and salicylate. Because of the serious side effects encountered with... 

Ethotoin. Chemically, 3-ethyl-5-phenylhy-dantoin, ethotoin (Ic) undergoes two biotransformation pathways leading to inactive products p-hydroxylation [pathway (1)] and deethylation [pathway (2)]. This product has relatively low potency compared to that of phenytoin. Like phenytoin, ethotoin displays saturable metabolism with respect to the formation of the two metabolites (18). 

Phenytoin is metabolized in the fiver by parahydroxylation. The major isoforms responsible for the metabolism of phenytoin are CYP2C9 and CYP2C19. Phenytoin displays Michaelis-Menton pharmacokinetics, which means that the metabolism of phenytoin saturates at doses used clinically. The clinical importance of this is that a small change in dose can result in a very disproportionally large increase in serum concentrations leading to potential toxicity. The metabolism of phenytoin may saturate even at low serum... 

I With zero-order kinetics (see Fig. 2.1) a fixed amount of drag is absorbed or ehminated for each unit of time independent of drag concentrations, because of some other rate-limiting factor. Examples are the metabolism of alcohol and phenytoin (saturation of metabolic enzymes) and absorption of controlled-release drags and depot antipsychotics. 

Both phenytoin and ethanol have saturable metabolism, which means an increase in dose results in a decrease in hepatic clearance and a more than proportional increase in AUC. In the remainder of this chapter, non-linearity in... 

Zero-order kinetics describe the time course of disappearance of drugs from the plasma, which do not follow an exponential pattern, but are initially linear (i.e. the drug is removed at a constant rate that is independent of its concentration in the plasma). This rare time course of elimination is most often caused by saturation of the elimination processes (e.g. a metabolizing enzyme), which occurs even at low drug concentrations. Ethanol or phenytoin are examples of drugs, which are eliminated in a time-dependent manner which follows a zero-order kinetic. 

Nonlinear relationship of phenytoin dosage and plasma concentrations. Five patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is saturable. Note also the marked variation among patients in the serum levels achieved at any dosage. 

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... 

Correct choice = D. Less than 5% of phenytoin is excreted unchanged in the urine it is metabolized by the hepatic hydroxylation system. Saturation of hepatic metabolizing enzymes at high doses of phenytoin leads to an increase in the half-life of the drug. 

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. 

Small amounts of phenytoin are excreted unchanged in the urine (2-4%) and feces (5%). Most is eliminated renally as inactive conjugated metabolites. The elimination half-life at linear doses averages 20-30 h (12-20 h in children) but may be as long as 60 h, and as high as 200 h after overdose, due to saturation of hydroxylation pathways. The maximum rate of metabolism is estimated at 6mgkg day. ... 

FIGURE 9.25 Nonlinear pharmacokinetics. Phenytoin demonstrates linear pharmacokinetics within a dose range (150 to 300 mg/day) until doses are attained that saturate its metabolism. At this point, the Css obtained by increases in dosage becomes nonlinear. From the previous linear relationship, a dosage of 450 mg/day would have been expected to produce a Css of 22.5 mg/L. However, saturation of phenytoin metabolism caused a massive increase in Css to 150 mg/L. 

Saturation of metabolism (capacity-limited metabolism) Phenytoin and ethanol saturate hepatic metabolism, showing decreased hepatic clearance with increased dose. 

Answer E. Back to basic principles. Zero-order elimination means that plasma levels of a drug decrease linearly with time. This occurs with ASA at toxic doses, with phenytoin at high therapeutic doses, and with ethanol at all doses. Enzymes that metabolize ASA are saturated at high plasma levels —> constant rate of metabolism = zero-order kinetics. Remember that application of the Henderson-Hasselbalch principle can be important in drug overdose situations. In the case of aspirin, a weak acid, urinary alkalinization favors ionization of the drug —>4 tubular reabsorption —>T renal elimination. 

Phenytoin induces liver enzymes and can affect the metabolism and activity of other drugs, anticoagulants for example. Liver enzymes can also be saturated which means that plasma levels of phenytoin can rise unpredictably as its inactivation slows down. 

Ethotoin differs from phenytoin in that one phenyl substituent at position 5 has been replaced by hydrogen, and the N-H at position 3 is replaced by an ethyl group (Fig. 20.5). It may be indicated for treatment of tonic-clonic and complex partial (psychomotor) seizures. Because it is considered to be less toxic but also less effective and more sedating than phenytoin, ethotoin usually is reserved for use as an add-on drug (39). Ethotoin does not share phenytoln s profile of antlarrhythmic action. The metabolism of ethotoin, like phenytoin, is saturable and nonlinear. Its administration Is contraindicated in patients with hepatic abnormalities and hematologic disorders. 

Not fully understood. The suggestion is that methylphenidate acts as an enzyme inhibitor, slowing the metabolism of the phenytoin by the liver and leading to its aeeumulation in those individuals whose drug metabolising system is virtually saturated by phenytoin. 

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