TABLE 3–1 Pharmacokinetic and pharmacodynamic parameters for selected drugs in adults. (See Holford et al, 2013, for parameters in neonates and children.) (Continued) 1Assuming creatinine clearance 100 mL/min/70 kg. 2Convert to mL/min by multiplying the number given by 16.6. 3Average steady-state concentration. 4Target area under the concentration-time curve after a single dose. 5Can be estimated from measured C using CL = Vmax/(Km + C); Vmax = 415 mg/d, Km = 5 mg/L. See text. 6Varies because of concentration-dependent clearance. 7Bound in whole blood (%). 8Based on whole blood standardized to hematocrit 45%.
CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action
TABLE 3–2 Physical volumes (in L/kg body weight) of some body compartments into which drugs may be distributed.
Compartment and Volume Examples of Drugs
Total body water Small water-soluble molecules: eg, ethanol Blood 0 Time (0.6 L/kg1)
Extracellular water Larger water-soluble molecules: eg, (0.2 L/kg) gentamicin Plasma (0.04 L/kg) Large protein molecules: eg, antibodies
Fat (0.2-0.35 L/kg)
Highly lipid-soluble molecules: eg, diazepam
Bone (0.07 L/kg) Certain ions: eg, lead, fluoride 1An average figure. Total body water in a young lean person might be 0.7 L/kg; in an obese person, 0.5 L/kg.
Added together, these separate clearances equal total systemic clearance: “Other” tissues of elimination could include the lungs and additional sites of metabolism, eg, blood or muscle.
The two major sites of drug elimination are the kidneys and the liver. Clearance of unchanged drug in the urine represents renal clearance. Within the liver, drug elimination occurs via biotransformation of parent drug to one or more metabolites, or excretion of unchanged drug into the bile, or both. The pathways of biotransformation are discussed in Chapter 4. For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination is directly proportional to concentration (rearranging equation [2]):
This is usually referred to as first-order elimination. When clearance is first-order, it can be estimated by calculating the area under the curve (AUC) of the time-concentration profile after a dose. Clearance is calculated from the dose divided by the AUC. Note that this is a convenient form of calculation—not the definition of clearance.
A. Capacity-Limited Elimination
For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance will vary depending on the