Capacity limited drugs

High-clearance drugs are those for which there is no saturation of the reaction that converts the drug, and therefore, the clearance rate approaches the blood-flow rate. For capacity-limited drugs, flow rate is irrelevant, and clearance is a simple product of the unbound fraction and the intrinsic clearance. 

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. 

Owing to capacity-limited drug-cell contacts, the bimolecular interaction in Eq. (23.5) can be modified, whereby the second-order rate constant k is replaced by a maximum value (f max) and a sensitivity parameter (AC50) reflecting the drug concentration producing 50% of (6) ... 

In calves and cows at high dose levels (100 SDM mg/kg), a biphasic elimination SDM plasma concentration-time curve was observed with a steady state plasma SCH2OH concentration resulting from the capacity limited hydroxylation of SDM into the latter. The drug concentrations in the milk reflected those in plasma. 

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. 

Because plasma protein and tissue binding influences the amount of drug in each body compartment, the volume of distribution of a drug may be dose dependent (nonhnear). A limited number of binding sites may result in capacity-limited binding in plasma or tissues. Transport from the blood may also be capacity limited. Examples of dose-dependent volume changes show that the volume of distribution of recombinant human tumor necrosis factor (TNF) alpha decreases sharply with a fourfold increase in dose and that the volume of distribution of recombinant human DNase,... 

For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance will vary depending on the concentration of drug that is achieved (Table 3-1). Capacity-limited elimination is also known as saturable, dose- or concentration-dependent, nonlinear, and Michaelis-Menten elimination. 

Renal failure will result in a diminished elimination of drugs that are primarily secreted, such as penicillins and aminoglycosides, and therefore in a longer half-life of the drug (45). Likewise, liver disease may result in a capacity-limited biotransformation, and consequently in a slower elimination of the drug. Bacterial pneumonia in calves may also result in increased serum oxytetracycline concentrations, a condition that can cause prolonged elimination (46). 

Limited drug loading capacity poor stoichiometry of drug to carrier limits the mass transport mediated by the drag carrier. 

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... 

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. 

The sophisticated structure and specialized function of airways and membranes in the nasal cavity, and also the small surface area of this region, may limit its capacity for drug delivery. The effect of chronic drug exposure on the integrity of nasal membranes must also... 

When the absorption is mediated by active transporters that are capacity limited, sustained presentation of the drug to the transporting enzymes may increase the efficacy of the transport and thus improves bioavailability. 

Figure 33-10 Dose-response curves. L/ne A illustrates the linear relationship between serum drug concentration and total daily dose of a drug that displays first-order kinetics typical of most drugs. Line B illustrates the dose-response relationship for a drug that displays capacity-limited kinetics because of a saturable enzyme or transport mechanism in this situation, serum concentration becomes independent of total daily dose, and the relationship of drug concentration to dose becomes nonlinear. (Modified from Pippenger CE. Practical pharmacokinetic appiications. Syvo Monitor, Son Jose Syva Co, January, i 979 1-4.)...

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