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FIGURE 1-3 Plasma concentration-time curves following intravenous administration of a drug (500 mg) to a 70kg patient. A. Drug concentrations are measured in plasma at 2-hour intervals following drug administration. The semi-logarithmic plot of plasma concentration (Cp) versus time appears to indicate that the drug is eliminated from a single compartment by a first-order process (Equation 1-7) with a ty2 of 4 hours (k = 0.693/tiy2 = 0.173 hr-1). The volume of distribution (V) may be determined from the value of Cp obtained by extrapolation to t = 0 (CpJ = 16 mg/mL). Volume of distribution (Equation 1-6) for the one-compartment model is 31.3 L, or 0.45 L/kg (V = dose/Cp|). The clearance for this drug is 90 mL/min; for a one-compartment model, CL = kV. B. Sampling before 2 hours indicates that, in fact, the drug follows multiexponential kinetics. The terminal disposition half-life is 4 hours, clearance is 84 mL/min (Equation 1-5), Varea is 29 L (Equation 1-7), and Vss is 26.8 L. The initial or "central" distribution volume for the drug (V1 = dose/C°) is 16.1 L. The example chosen indicates that multicompartment kinetics may be overlooked when sampling at early times is neglected. In this particular case, there is only a 10% error in the estimate of clearance when the multicompartment characteristics are ignored. For many drugs, multicompartment kinetics may be observed for significant periods of time, and failure to consider the distribution phase can lead to significant errors in estimates of clearance and in predictions of the appropriate dosage. Also, the difference between the "central" distribution volume and other terms reflecting wider distribution is important in deciding a loading dose strategy. The multi-compartment model of drug disposition can be viewed as though the blood and highly perfused lean organs such as heart, brain, liver, lung, and kidneys cluster as a single central compartment, whereas more slowly perfused tissues such as muscle, skin, fat, and bone behave as the final compartment (i.e., the tissue compartment). If the ratio of blood flow to various tissues changes within an individual or differs among individuals, rates of drug distribution to tissues will change. Changes in blood flow may cause some tissues that were originally in the "central" volume to equilibrate so slowly as to appear only in the "final" volume. This means that central volumes will appear to vary with disease states that cause altered regional blood flow (e.g., liver cirrhosis). After an intravenous bolus dose, drug concentrations in plasma may be higher in individuals with poor perfusion (e.g., shock). These higher systemic concentrations, in turn, may cause higher concentrations (and greater effects) in highly perfused tissues such as brain and heart. Thus, the effect of a drug at various sites of action can vary depending on perfusion of these sites.

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