PHARMACOKINETICS AND PHARMACODYNAMICS OF PENBUTOLOL IN HEALTHY AND CANCER SUBJECTS - ROLE OF ALTERED PROTEIN-BINDING

The pharmacokinetic and pharmacodynamic profiles of penbutolol were ex amined in healthy volunteers and in cancer patients using a pharmacoki netic/pharmacodynamic (pk/pd) model. After receiving a 40 mg single or al dose of penbutolol, the absorption rate constant, apparent volume o f distribution and serum clearance of penbutolol were found to be redu ced in the cancer group. Changes in the disposition of the conjugate m etabolite were also observed in the cancer patients. Penbutolol unboun d fraction in serum was statistically decreased (p < 0.005) in the can cer group, according to the increase in the serum levels of alpha(1)-a cid glycoprotein seen in that group (p < 0.05). The pharmacodynamic ef fect of penbutolol was measured as the reduction in heart rate (HR); i n healthy volunteers, a linear relationship (p < 0.01) between effect and penbutolol serum concentrations (total or unbound) was found. In c ontrats, in cancer patients, values of HR did not vary statistically i n respect to baseline values. These results show that in cancer patien ts, a change in the pharmacokinetics of penbutolol occurs (associated with changes in drug protein binding), together with an alteration in the pharmacodynamics.