Phenytoin kinetics

You will need to check the plasma concentration you achieve because the patient s phenytoin kinetics may differ from the average, but you will not be out by much and will have the confidence of having derived the dose in a logical and defensible way. 

Paxton JW. Effects of aspirin on salivary and serum phenytoin kinetics in healthy subjects. Clin Phannacol Ther 1980 27 170-178. 

Blaschke TF, Meffin PJ, Melmon KL, et al. (1975) Influence of acute viral hepatitis on phenytoin kinetics and protein binding. Clin Pharmacol Ther 17 685-691. 

TABLE 5.3 Effect of Impaired Renal Function on Phenytoin Kinetics... 

Bauer LA, Blouin RA. Age and phenytoin kinetics in adult epileptics. Clin Pharmacol Ther 1982 31 301-4. 

Furlanut M, Benetello P, Avogaro A, Dainese R. Effects of folic acid on phenytoin kinetics in healthy subjects. Clin Pharmacol Ther 1978 24(3) 294-7. 

Iteogu MO, Murphy JE, Shleifer N, Davis R Effect of cimetidine on single-dose phenytoin kinetics. Clin Pharm (1983) 2, 302. ... 

Bartie WR, Walker SE, Shapero T. Dose-dependent effect of cimetidine on phenytoin kinetics. Clin Pharmacol 77r r(1983) 33, 649-55. 

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. 

Phenytoin is metabolized in the liver mainly by CYP2C9, but CYP2C19 is also involved. Zero-order kinetics occurs within the usual therapeutic range, so any change in dose may produce disproportional changes in serum concentrations. 

There are comparatively few studies addressing the structure-metabolism relationships of phosphoric acid monoester hydrolysis. For example, kinetics of decomposition in rat whole blood were examined for the phosphoric acid monoesters of estrone, 17a- and 17/J-testosterone, 3-(hydroxyme-thyl)phenytoin (see Fig. 9.7,a), and 1-phenylvinyl alcohol (9.28, the enolic form of acetophenone) [87]. As a general trend, the rate of hydrolysis increased with the acidity of the leaving hydroxylated compound. In other words, hydrolysis was the fastest for the phosphoric acid aryl monoester (estrone 3-phosphate), and slowest for the two testosterone phosphoric acid... 

In previous chapters, we discussed the hydrolysis of a number of esters of A-(hydroxymethyl)phcnytoin, namely esters of organic acids (7V-acyloxy-methyl derivatives, Sect. 8.7.3) or inorganic acids (Sect. 9.3.2). Hydrolysis of these potential prodrugs released 3-(hydroxymethyl)phenytoin (11.45), whose breakdown to phenytoin and formaldehyde was also investigated per se [79], The latter reaction followed pseudo-first-order kinetics. At pH 7.4, the f1/2 values were 4.7 and 1.6 s at 25° and 37°, respectively. The tm values decreased tenfold for each increase of pH by one unit, which, together with the absence of any buffer catalysis, indicates catalysis by the HO- anion. 

In all this, it should be remembered that the role of regulatory authorities is to protect the public. For entirely justifiable reasons, they will apply very strict criteria to products with a low therapeutic index, non-linear kinetics or imfavour-able physical properties. Digoxin, phenytoin and primidone provide notable examples of drugs where bioinequivalence issues have led to clinical problems. 

B. Phenytoin is one of a handful of drugs that demonstrates zero-order (or saturation) kinetics. If a patient is showing signs of toxicity to phenytoin, it is important to measure blood levels, since the likelihood that phenytoin is demonstrating zero-order kinetics is very high. 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

The elimination of phenytoin is dose-dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached. Further increases in dosage, though relatively small, may produce very large changes in phenytoin concentrations (Figure 24-5). In such cases, the half-life of the drug increases markedly, steady state is not achieved in routine fashion (since the plasma level continues to rise), and patients quickly develop symptoms of toxicity. 

Modified, with permission, from Jusko WJ Bioavailability and disposition kinetics of phenytoin in man. In Kellaway P, Peterson I [editors] Quantitative Analytic Studies in Epilepsy. Raven Press, 1977.)... 

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... 

Nonlinear pharmacokinetics. Nonlinear pharmacokinetics simply means that the relationship between dose and Cp is not directly proportional for all doses. In nonlinear pharmacokinetics, drug concentration does not scale in direct proportion to dose (also known as dose-dependent kinetics). One classic drug example of nonlinear pharmacokinetics is the anticonvulsant drug phenytoin.38 Clinicians have learned to dose pheny-toin carefully in amounts greater than 300 mg/day above this point, most individuals will have dramatically increased phenytoin plasma levels in response to small changes in the input dose. 

Nonlinear relationship of phenytoin dosage and plasma concentrations. Five different 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. (Modified, with permission, from Jusko WJ Bioavailability and disposition kinetics of phenytoin in man. In Kellaway P, Peterson I [editors]. Quantitative Analytic Studies in Epilepsy. Raven Press, 1977.)... 

Minimizing the problems caused by the non-linear kinetics of the drug (e.g. phenytoin). 

Phenytoin is an anticonvulsant that has been shown to be preferentially hydroxy-lated in the pro-(.S ) ring by CYP2C9 (77), which accounts for approximately 80% of its clearance in man (78). The use of phenytoin is complicated by virtue of its nonlinear kinetics, long half-life, and narrow therapeutic margin. However, it has been used to confirm the in vitro finding that phenytoin and tolbutamide are metabolized by the same P450 enzyme (79). 

UGT1A6 is a high-affinity (Km = 2.2 mM), low-capacity enzyme. UGT1A1 has intermediate affinity (9 mM) with high capacity, and UGT1A9 is a low-affinity, high-capacity enzyme (21 mM) (59). With a kinetic model, Court et al. estimated that at typical therapeutic concentrations (0.05-5 mM), UGT1A9 was the most important enzyme (>55% of total activity). Consequently, the mechanism of induction by oral contraceptives, phenytoin, and rifampin is unclear and may involve multiple enzymes. 

Zero-order kinetics With a few drugs, such as aspirin (see p. 407), ethanol and phenytoin (see p. 146), the doses are very large, so the [C] is much greater than Km, and the velocity equation becomes ... 

Consider the difference in response to drugs between older and younger people. Treatment should reflect biological age (rather than chronological). Pharmacokinetics, pharmacodynamics, tolerability, adverse reactions, economy and patient choice will all influence therapy chosen. Most commonly, car-bamazepine or sodium valproate are chosen for older people as their effects in older people are well documented. Both show a favourable balance of safety, efficacy and economy. Phenytoin is less preferable because of drug interactions, adverse effects and potential for toxicity (zero order kinetics). 

---