Liver, drug elimination

The mass transfer coefficients may also be expressed in units of time-1 by multiplying by the appropriate compartmental volume term. Irreversible drug elimination from the tissue requires the addition of an expression to the differential equation that represents the subcompartment in which elimination occurs. For instance, hepatic drug elimination would be described by a linear or nonlinear expression added to the intracellular liver compartment mass balance equation since this compartment represents the hepatocytes. Formal elimination terms are given below for the simplified tissue models. 

Figure 15.1 Schematic illustration of the extended phase concept during drug elimination in the kidney and liver. Phase 0 = uptake of drugs from the blood into the hepatocytes or proximal tubule epithelial cells. This uptake is mediated by transport proteins belonging to the SLC (solute carrier) transporter superfamily. Phase I and...

Smith, N. F., Figg, W. D., and Sparreboom, A. (2005) Role of the liver-specific transporters OATPIBI and OATP1B3 in governing drug elimination. Expert Opin. Drug Metab. Toxicol. 1, 429-445. 

The clearance of a drug is usually defined as the rate of elimination of a compound in the urine relative to its concentration in the blood. In practice, the clearance value of a drug is usually determined for the kidney, liver, blood or any other tissue, and the total systemic clearance calculated from the sum of the clearance values for the individual tissues. For most drugs clearance is constant over the therapeutic range, so that the rate of drug elimination is directly proportional to the blood concentration. Some drugs, for example phenytoin, exhibit saturable or dose-dependent elimination so that the clearance will not be directly related to the plasma concentration in all cases. 

The pharmacokinetic term clearance (CT) best describes the efficiency of the elimination process. Clearance by an elimination organ (e.g., liver, kidney) is defined as the volume of blood, serum, or plasma that is totally cleared of drug per unit time. This term is additive the total body or systemic clearance of a drug is equal to the sum of the clearances by individual eliminating organs. Usually this is represented as the sum of renal and hepatic clearances CT = CT renal -I- CL hepatic. Clearance is constant and independent of serum concentration for drugs that are eliminated by first-order processes, and therefore may be considered proportionally constant between the rate of drug elimination and serum concentration. 

The most important processes assessed in pharmacokinetic studies are absorption (uptake of a drug from the digestive tract), distribution (compart-mentalization in the body), metabolism (conversion or breakdown, especially in the liver) and elimination (excretion), summarized by the abbreviation ADME. 

In congestive heart failure the drug elimination is retarded due to decreased perfusion and congestion of liver, also reduced glomerular filtration and increased tubular reabsorption. 

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 ... 

Depending on the individual drug, elimination occurs primarily through excretion from the lungs, biotransformation in the liver, or a combination of these two methods.39 If the patient has any pulmonary or hepatic dysfunction, elimination of the anesthetic will be further delayed. 

The liver is the principal metabolic organ, and hepatic disease or dysfunction may impair drug elimination. Any alteration in the serum albumin or bilirubin levels and in the prothrombin time indicates impaired liver function. Similarly, skin bruising and bleeding tendency indicate decreased production of clotting factors by the liver. 

Imatinib is administered orally and is well absorbed it is highly protein-bound in plasma. The drug is metabolized in the liver, and elimination of metabolites occurs mainly in feces via biliary excretion. This agent is approved for use as first-line therapy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior interferon- therapy. Imatinib is effective also for treatment of gastrointestinal stromal tumors expressing the c-kit tyrosine kinase. Dosage and toxicities are listed in Table 55-6. 

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