Absence of genotoxic activity of penbutolol in bacterial and mammalian cell screening systems.

The genotoxic potential of the beta-adrenergic blocker penbutolol was assessed using the Ames and HGPRT tests, unscheduled DNA synthesis (UDS) and alkaline elution assays. In the Ames test, penbutolol was tested for cytotoxicity and genotoxic activity in concentration ranges of 0.8-500 micrograms/plate and 0.1-125 micrograms/ml in the HGPRT, UDS and alkaline elution assays. In the Ames test penbutolol showed significant toxicity above 500 micrograms/plate. In the mammalian cells (V79) used for the HGPRT test and A459 cells used for alkaline elution and UDS assays, penbutolol was cytotoxic at concentrations above 30 micrograms/ml. In another series of experiments, male Wistar rats were treated i.p. with penbutolol (1, 10 and 100 mg/kg) and after 2 h liver nuclei were isolated and formation of single DNA-strand breaks was measured. The results of the present study demonstrate the absence of genotoxic activity of penbutolol in the 5 strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA1538) and in the strain of Escherichia coli WP2 uvrA in the presence or absence of metabolic activation. In V79 cells, penbutolol showed no mutagenic effects at the HGPRT locus in the presence or absence of metabolic activation. Additionally, no significant incorporation of [3H]thymidine into the DNA in the UDS test or formation of DNA-strand breaks in the alkaline elution assay was detected in the non-toxic concentration range of penbutolol with or without metabolic activation. Furthermore, penbutolol did not cause DNA damage in liver nuclei isolated from penbutolol-treated rats.

Mutagenicity of enantiomers of penbutolol.

With a view to examine the effect of chirality and the cause of batch-to-batch variation in the mutagenicity of penbutolol, penbutolol enantiomers - isopenbutolol [R(+)-enantiomer] and penbutolol [S(-)-enantiomer] - and two batches of Betapressin were tested employing the Ames Salmonella tester strain TA98. The mutagenic activity of R(+)-enantiomer was found to be similar to that of a batch of penbutolol with a high content of this optical isomer. The pharmaceutical form of penbutolol, Betapressin, exhibited either less or equal mutagenic effectiveness to the S(-)-enantiomer. In the presence of the S9 mix, the mutagenicity of R(+)-enantiomer was only slightly affected in the low dose range of 40 to 160 micrograms/plate. A metabolite of penbutolol, (RS) l"-dehydropenbutolol, did not cause an increase in the number of revertants/plate.

[On the pharmacology of the beta-receptor blocker penbutolol (author's transl)]. / Zur Pharmakologie des beta-rezeptorenblockers penbutolol.

1-tert.-Butylamino-3-(2-cyclopentylphenoxy)-propan-2-ol (penbutolol, Hoe 893d) is a beta-adrenergic blocking agent about 4 times more active than propranolol in vivo and in vitro. In comparison to propranolol it is characterized by a longer lasting activity. The antihypertensive effect of penbutolol in spontaneously hypertonic rats is more than 5 times stronger than that of propranolol. Penbutolol reduces basal plasma renin activity in the same dose range as does propranolol but is about 3 times stronger with respect to isoproterenol-induced increase of PRA. Penbutolol is 5 times more potent than propranolol inhibiting isoproterenol-stimulated phosphorylase activity in the isolated heart. In reserpine pretreated rats, penbutolol has a moderate intrinsic sympathomimetic activity (ISA). Penbutolol shows less unspecific actions -- such as negative inotropy or calcium antagonism -- than propranolol. Characteristic parameters of lung function (compliance and resistance) are less affected by penbutolol than propranolol in spite of the fact that penbutolol has a stronger beta-adrenergic blocking effect.