Metabolic rate of phenacetin and of paracetamol in dogs before and after treatment with phenobarbital or skf 525 A

In six male mongrel dogs the apparent biological half life ($\text{t}\text{2}$) in plasma of intravenously injected phenacetin decreased from 34·6 to 27·2 min after treatment with phenobarbital (25 mg/kg/day for 8 days) (P < 0·025). In the same dogs, the apparent $\text{t}\text{2}$ of intravenously injected phenazone decreased from 78·6 to 32·4 min (P < 0·05). Treatment with SKF 525 A (25 mg/kg) increased the $\text{t}\text{2}$ of phenazone in three other dogs from 70·6 to 246·7 min, whereas the $\text{t}\text{2}$ of phenacetin remained unaffected.The concentration of phenacetin at zero time of intravenous injection increased from 29·5 ± 5·9 S.E. to 43·5 ± 12·6 μg/ml plasma (P < 0·2) after phenobarbital treatment; pretreatment with phenobarbital, however, had no influence on the mean concentration of phenazone at 0 time. SKF 525 A did not influence the zero time concentration of either phenacetin or phenazone.Beagle liver microsomal protein and cytochrome P-450 concentrations increased from 3·2 to 4·2 mg/ml and from 1·0 to 4·1 n-mole/mg protein, respectively, after phenobarbital treatment. Treatment with phenobarbital had no influence on the rates of formation of paracetamol and p-phenetidin nor was the apparent K_m of phenacetin affected.The binding of phenacetin to blood constituents increased from 50 per cent at 5 μg/ml to 59 per cent at 1 μg phenacetin/ml. In the presence of 30 μg phenobarbital/ml blood, the binding of phenacetin at 1 μg/ml blood decreased by 22 per cent.It is concluded that the decrease of the apparent $\text{t}\text{2}$ of phenacetin in dog plasma after phenobarbital treatment may be due to a change in the apparent volume of distribution and/or to some stimulation of an NADPH-dependent enzyme system of the liver less affected by treatment with SKF 525 A than in other species.