There is confusion regarding the calculation of serum creatine kinase (CK) activity clearance from an elimination rate constant and a distribution volume derived from one- and two-compartment serum enzyme elimination models. We measured serum CK activity clearance from hepatic enzyme extraction and compared this direct measurement with clearance calculated assuming one- and two-compartment elimination models after bolus and constant infusions of a purified preparation of the MM isoenzyme of CK (MM-CK) activity. Although serum CK activity appears to confer on the body the characteristics of first-order disposition from two compartments, clearance is estimated equally well by one-, two-, and noncompartmental models of disposition and is essentially identical to the hepatic clearance of CK activity. As long as the rate constant and distribution volume are compatible and appropriate for a given elimination model, clearance, the product of the two, will be properly estimated regardless of the model chosen.