Capacity-limited metabolism

Capacity-limited metabolism is also called saturable metabolism, Michaelis-Menten kinetics or mixed-order kinetics. The process of enzymatic metabolism of drugs may be explained by the relationship depicted below 

Enzyme + Substrate (drug)- Enzyme-drug complex Enzyme + Metabolite 

Eirst the drug interacts with the enzyme to produce a drug-enzyme intermediate. Then the intermediate complex is further processed to produce a metabolite, with release of the enzyme. The released enzyme is recycled back to react with more drug molecules. 

According to the principles of Michaelis-Menten kinetics, the rate of drug metabolism changes as a function of drug concentration, as illustrated in Fig. 15.5. 

Based on this relationship, at very low drug concentration, the concentration of available enzymes is much greater than the number of drug molecules or the drug concentration. Therefore, when the concentration of drug is increased, going from left to right in Fig. 15.5, the rate of metabolism is also increased proportionally 

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Capacity-Limited Metabolism For some drugs clearance changes with the drug concentration. Increases in maintenance doses will result in a disproportionate increase in the steady-state drug concentration. Phenytoin is the classic capacity-limited drug. 

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

The equation derived above (Eq. 15.9) can be used to derive two steady-state drug concentrations (e.g. for a drug such as phenytoin, which undergoes capacity-limited metabolism) arising from two infusion rates ... 

There is only a limited capacity to metabolize vitamin A, and excessive intakes lead to accumulation beyond the capacity of binding proteins, so that unbound vitamin A causes tissue damage. Symptoms of toxicity affect the central nervous system (headache, nausea. 

PBPK and classical pharmacokinetic models both have valid applications in lead risk assessment. Both approaches can incorporate capacity-limited or nonlinear kinetic behavior in parameter estimates. An advantage of classical pharmacokinetic models is that, because the kinetic characteristics of the compartments of which they are composed are not constrained, a best possible fit to empirical data can be arrived at by varying the values of the parameters (O Flaherty 1987). However, such models are not readily extrapolated to other species because the parameters do not have precise physiological correlates. Compartmental models developed to date also do not simulate changes in bone metabolism, tissue volumes, blood flow rates, and enzyme activities associated with pregnancy, adverse nutritional states, aging, or osteoporotic diseases. Therefore, extrapolation of classical compartmental model simulations... 

In chickens a pattern similar to a capacity limited-elimination was noticed. The cause may be either a capacity limitation in the SDM metabolism (hydroxylation ) of SDM or extensive drug reabsorption from the cloaca occurring at night(known as chrono-pharma-cokinetics). In the chicken, 58 % of the intravenously administered dose is lost, which is also reported for other birds (24). Thus birds must possess additional metabolic pathways. 

Genetic polymorphism may result in poor metabolizers (i.e., individuals who have only a limited or no capacity to metabolize a given chemical via a specific enzymatic pathway), and extensive metabolizers (i.e., individuals who have a sufficient capacity to metabolize a given chemical via a specific enzymatic pathway) and individuals of a particular group may therefore respond differently to exposure to chemicals. 

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. 

Disposition in the Body. Slowly but almost completely absorbed after oral administration the rate of absorption is variable, being prolonged after large doses, and the bioavailability may vary considerably between different formulations. Aromatic hydroxylation is the major metabolic pathway and about 50 to 70% of a dose may be excreted as free or conjugated 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) in 24 hours the excretion of this metabolite is dose-dependent and decreases as the dose is increased. Phenytoin hydroxylation is capacity-limited, and is therefore readily inhibited by agents which compete for its metabolic pathways. Less than 5% of a dose is excreted as unchanged drug. Minor metabolites include 5-(3-hydroxyphenyl)-5-phenylhydantoin, 3,4-dihydro-3,4-dihydroxy-phenytoin, catechol, and 3-D-methylcatechol. Up to about 15% of a dose may be eliminated in the faeces. 

This biotransformation process takes place principally in the liver, i.e. in the smooth endoplasmic reticulum, partly also in the mitochondria. The kidneys, lungs, intestine, muscles, spleen and skin are involved to a lesser degree in biotransformation. Through hydrolysis and reduction, the intestinal flora may also play a role in this metabolic process. Biotransformation is limited by the hepatic blood flow (= flow-limited elimination) and by the capacity of microsomal enzyme systems (= capacity-limited elimination). (80, 95)... 

The host-mediated assay (HMA), developed in the late 1960s by Gabridge and Legator, is an approach for providing the in vivo metabolism of a whole animal (the host) for assessing effects on indicator cells that have been placed in the host during chemical exposure and then subsequently removed for in vitro measurements of mutagenicity. Due to the limited metabolic capacity of most bacterial and mammalian... 

Phenytoin. Phenytoin (l s slowly absorbed from the small intestine. The rate, extent, and bioavailability vary because of the manufacturer s formulation process. Intramuscular injection tends to precipitate at the site of injection, resulting in erratic plasma levels these levels are significantly lower than those obtained by the oral route. Phenytoin is metabolized in the liver to inactive hydroxylated metabolites (see Fig. 6.3) (20). For a complete discussion, the reader is referred to the earlier edition of this chapter (8).The metabolism of phenytoin is capacity limited and shows satu-rability. Because the elimination of the p-hy-dro glucuronide metabolite is rate limited by its formation from phenytoin, measure-... 

GBL was found to hydrolyse rapidly in plasma, with a half-life of approximately 1 minute. In spite of this rapid biotransformation, oral activity of GBL was almost identical to that achieved after intravenous administration of GHB. Apparently, GBL is not subjected to any of the processes which decrease peak plasma concentrations, viz gastrointestinal degradation, capacity-limited transport and first-pass metabolism. The use of lactone analogs as a general approach to improve the bioavailability and/or rate of absorption of other hydroxy-acids, e.g. prostaglandins, has, however, not been tested. 

Absorption of GHB has been shown to be a capacity-limited process with increases in dose resulting in increases in time to peak concentration. The concentration in brain equilibrates with other tissues after approximately 30 min. GHB crosses the placental barrier at a similar rate to that in the blood-brain barrier (Van der Pol et al., 1975). GHB also exhibits hrst-pass metabolism when given orally with about 65% bioavailability when compared with an equivalent intravenous dose. 

If Clint is small (enzymes have a limited capacity to metabolize the drug), Q is much larger than the product of/b and Clim. When Q... 

When single doses of 100, 200, 400, 600, 800, and 1200 mg of clarithromycin were compared in healthy subjects, the pharmacokinetics of the parent drug and metabolite were nonlinear [51], with apparent capacity-limited formation of the 14-(i )-hydroxy metabolite at doses of >600 mg. Nonlinear kinetics were also seen in studies of single and multiple doses of clarithromycin, where increases in C ,ax and AUC of the parent drug were more than proportionate with the dosages [52]. In another study, the AUC for clarithromycin increased 13-fold, with a 4.8-fold increase in dose. Pharmacokinetic data suggest that nonlinearity was due predominantly to a decrease in the apparent metabolic clearance, which fell from 913 to 289 ml/min (Table II) [50]. 

Dosage Levels for Metabolism and Toxicology Studies. Administration of doses above those which saturate metabolic systems or the capacity-limited elimination rate in the test species can cause toxic effects which do not occur at lower dosage levels. This saturation can be the most sensitive indicator of overdosing and should be taken into consideration in choosing the Maximum Tolerated Dose (MTD) for toxicity studies. Toxicological effects generated in overdosed animals may simply be artifacts from which valid extrapolations to potential effects in humans cannot be made. 

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