Total systemic clearance

CLi = organ clearance fi = fraction of dose eliminated by organ i CL = total systemic clearance... 

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. 

In the broadest sense, total (systemic) clearance is the clearance of drug by all routes. Total (systemic) clearance (Cl) can be calculated by either of the equations given below ... 

Clearance may also be viewed as the loss of drug from an organ of elimination such as the liver or kidney. This approach enables evaluation of the effects of a variety of physiological factors such as changes in blood flow, plasma protein binding, and enzyme activity. Therefore, total systemic clearance is determined by adding the clearance (CL) values for each elimination organ or tissue ... 

Tasidotin total systemic clearance did not change over day of administration, but did decrease with increasing dose (p <0.0001) and increased with increasing... 

BSA (p <0.0001). The least-squares mean clearance for a patient with a BSA of 1.83 m2 at 2.3 mg/m2 was 62 L/h, but was 30 L/h at 62.2 mg/m2. Decreasing clearance with increasing dose is consistent with Michaelis-Menten elimination kinetics. Between-subject variability was moderate at approximately 30%. Tasidotin did not show any major renal elimination, with only ca. 13% of the dose being found in the urine as unchanged drug. In Study 103, the least-squares mean tasidotin renal clearance was approximately 4.3 L/h (about 13% of total systemic clearance), with a between-subject variability of approximately 51%. Given a glo-... 

The least-squares mean tasidotin total volume of distribution at steady state was 10 L, and was not affected by dose or day of administration. Between-subject variability was estimated at 39%. The tasidotin half-life did not change over day of administration, but increased with increasing dose (p < 0.0001) and decreased with increasing BSA (p = 0.0144). The least squares mean half-life was 26 min at 2.3 mg/m2, but was 46 min at 62.2 mg/m2. Between-subject variability was estimated at approximately 20%. The finding that the half-life was dose-dependent was not surprising, as total systemic clearance was affected by both dose and BSA, whereas volume of distribution at steady state was unaffected by dose or BSA. Under these conditions, the half-life would be expected to change inversely proportional to clearance. 

After intravenous administration, paclitaxel is extensively distributed, despite extensive binding to plasma proteins (89%), presumably albumin (2). Its routes of elimination have not been fully elucidated, but renal clearance accounts for an insignificant proportion of total systemic clearance, suggesting that metabolism, biliary excretion, or excretion via other routes are responsible for elimination (6). High concentrations of paclitaxel and its hydroxylated metabolites have been found in rat and human bile, suggesting hepatic metabolism (8). In all, 11 metabolites of paclitaxel have been identified, and paclitaxel metabolism to 6-a-hydroxypaclitaxel is an important detoxification pathway (6,9). 

The total systemic clearance is the sum of clearance by all mechanisms (e.g. renal, hepatic, etc.). Clearance is defined as the volume of plasma that is completely depleted of drug per unit time to account for the rate of elimination. It is usually constant for a drug, within the desired clinical concentrations, but does not indicate how much drug is being removed. 

Hence, intravenous data were modeled first, followed by inhalational, then intranasal. Once the pharmacokinetics of each individual route of administration was established, all model parameters were then estimated simultaneously. Initial values for cocaine pharmacokinetics after intravenous administration were estimated using noncompartmental methods. Total systemic clearance was estimated at 100 L/h and volume of distribution at steady-state was estimated at 232 L. Central compartment clearance and intercompartmental clearance were set equal to one-half total systemic clearance (50 L/h), whereas central and peripheral compartment volumes were set equal to one-half volume of distribution (116 L). Data were weighed using a constant coefficient of variation error model based on model-predicted plasma concentrations. All models were fit using SAAM II (SAAM Institute, Seattle, WA). An Information-Theoretic approach was used for model selection, i.e., model selection was based on the AIC. 

Primary pharmacokinetic parameters such as total systemic clearance (CL) and the volume of distribution at steady state (U ) can be defined as ... 

Figure 3.2-4. Interspecies scaling of total systemic clearance (CL top panel) and steady-state volume of distribution (Vjs bottom panel) of interferon-a as a function of total body weight. Species include mouse ( ), rat ( ), rabbit ( ), African green monkey (A), dog ( ), and human (O). Human values were not included in the line of regression, and data were obtained from Lave et al. [78],...

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