Disposition of propranolol VI. Independent variation in steady‐state circulating drug concentrations and half‐life as a result of plasma drug binding in man

Plasma binding of propranolol has been measured at therapeutic concentrations in 6 subjects in whom steady‐state blood concentrations and half‐life had been measured during chronic oral administration of 80 mg every 6 hours. Neither steady‐state blood concentrations nor drug clearance (Cl ** ) was related to binding of drug in the blood. Volume of distribution (Vd β ), however, increased as the fraction of free drug in the blood (fb) increased, such that the volume of distribution of free drug (Vdp/fb) was relatively constant. Drug half‐life was proportional to fb/Cl ** since it was a function of both Vdp and clearance that varied independently. These data show that propranolol can be classified as a drug whose hepatic elimination is not restricted to the free drug in the circulation, so that binding to elements in the blood accelerates its elimination rate by acting as a carrier system from the tissues to its site of elimination and that this occurs without alteration drug clearance or steady‐state total blood concentrations.