Decrease in penbutolol protein binding as a consequence of treatment with some alkylating agents

The effect of in vitro treatment of serum with the alkylating agents carmustine (BCNU) and mechlorethamine on the protein binding of penbutolol, a basic agent mainly bound to alpha₁-acid glycoprotein (AAG), was investigated. The free fraction of penbutolol increased significantly (P<0.001) after the treatment of serum with BCNU (5.27%±0.47%) and with mechlorethamine (5.23% ±0.17%), being 1.98%±0.18% in serum not treated with BCNU or mechlorethamine. In addition, after incubation with BCNU (2 h), the free fraction of penbutolol continued increasing (10.96%±0.70% vs 5.27%±0.47% at time 0;P<0.001), whereas it remained unchanged after incubation with mechlorethamine. Moreover, dialysis against saline for 24 h did not restore the free fraction of penbutolol, which increased after treatment with carmustine (9.05%±1.24% vs. 11.04%±1.55%, nondialyzed). We concluded that the treatment of cancer patients with alkylating agents could alter the serum proteins and modify their binding capacity, and this should be taken into account in the simultaneous treatment of these patients with other basic drugs like penbutolol, e.g., methadone.