Two-Compartment Open Model PDF

TWO-COMPARTMENT OPEN MODEL Chapter 5 Dr. Fatima A Tawfiq  TWO-COMPARTMENT OPEN MODEL The plasma level–time curve for a drug that follows a two- compartment model shows that the plasma drug concentration declines biexponentially as the sum of two first-order processes— dis...

TWO-COMPARTMENT OPEN MODEL Chapter 5 Dr. Fatima A Tawfiq  TWO-COMPARTMENT OPEN MODEL The plasma level–time curve for a drug that follows a two- compartment model shows that the plasma drug concentration declines biexponentially as the sum of two first-order processes— distribution and elimination. A drug that follows the pharmacokinetics of a two-compartment model does not equilibrate rapidly throughout the body, as is assumed for a one- compartment model. In this model, the drug distributes into two compartments, the central compartment and the tissue, or peripheral, compartment. The drug distributes rapidly and uniformly in the central compartment. A second compartment, known as the tissue or peripheral compartment, contains tissues in which the drug equilibrates more slowly.  Drug transfer between the two compartments is assumed to take place by first-order processes. 50 a 10 5 b 1 0 3 6 9 12 Time  compartment 1 is the central compartment and compartment 2 is the tissue compartment. The rate constants k12 and k21 represent the first-order rate transfer constants for the movement of drug from compartment 1 to compartment 2 (k12) and from compartment 2 to compartment 1 (k21). Most two-compartment models assume that elimination occurs from the central compartment model Drug elimination is presumed to occur from the central compartment, because the major sites of drug elimination (renal excretion and hepatic drug metabolism) occur in organs such as the kidney and liver, which are highly perfused with blood.  The two-compartment model assumes that, at t = 0, no drug is in the tissue compartment. After an IV bolus injection, drug equilibrates rapidly in the central compartment. The distribution phase of the curve represents the initial, more rapid decline of drug from the central compartment into the tissue compartment (line a). At maximum tissue concentrations, the rate of drug entry into the tissue equals the rate of drug exit from the tissue. The fraction of drug in the tissue compartment is now in equilibrium (distribution equilibrium). The drug concentrations in both the central and tissue compartments decline in parallel and more slowly compared to the distribution phase. This decline is a first-order process and is called the elimination phase or the beta (b) phase (line b).  300 200 100 50 Plasma 10 5 Tissue 1 Time Relationship between tissue and plasma drug concentrations for a two-compartment open model. ❑ drug concentrations may vary among different tissues and possibly within an individual tissue. These varying tissue drug concentrations are due to differences in the partitioning of drug into the tissues. ❑ Moreover, the elimination rates of drug from the tissue compartment may not be the same as the elimination rates from the central compartment. ❑ For example, if k12·Cp is greater than k21·Ct (rate into tissue > rate out of tissue), tissue drug concentrations will increase and plasma drug concentrations will decrease.  Cp = Ae−αt + Be−βt The constants a and b are rate constants for the distribution phase and elimination phase, respectively. The constants A and B are intercepts on the y axis for each exponential segment of the curve. These values may be obtained graphically by the method of residuals.  Method of Residuals The method of residuals is a useful procedure for fitting a curve to the experimental data of a drug when the drug does not clearly follow a one-compartment model. For example, 100 mg of a drug was administered by rapid IV injection to a healthy 70-kg adult male. Blood samples were taken periodically after the administration of drug: Plasma Concentration (μg/mL) Time (hour) 0.25 43.00 0.5 32.00 1.0 20.00 1.5 14.00 2.0 11.00 4.0 6.50 8.0 2.80 12.0 1.20 16.0 0.52  𝐶𝑝 = 𝐵𝑒−𝑏𝑡 −𝑏𝑡 50 𝑙𝑜𝑔𝑐𝑃 = + 𝑙𝑜𝑔𝐵 C p = 45 e –1.8t + 15 e –0.21t 2 3 10 0.693 5 𝑡1 = 2 𝑏 a b 1 𝑎𝑏(𝐴 + 𝐵) 0.5 𝑘= 𝐴𝑏 + 𝐵𝑎 0.1 0 4 8 12 16 Time (hours)  Time Cp Observed Plasma Level Cp Extrapolated Cp – Cp Residual (hour) Plasma Plasma Concentration Concentration 0.25 43.0 14.5 28.5 0.5 32.0 13.5 18.5 1.0 20.0 12.3 7.7 1.5 14.0 11.0 3.0 2.0 11.0 10.0 1.0 4.0 6.5 8.0 2.8 12.0 1.2 16.0 0.52