INTERACTION OF DIPHENYLHYDANTOIN (PHENYTOIN) AND PHENOBARBITAL WITH HORMONAL MEDIATION OF FETAL RAT BONE-RESORPTION INVITRO

To examine the direct action of anticonvulsant drugs on bone resorption, the authors investigated the effects of diphenylhydantoin (phenytoin) (DPH) (100-200 μg/ml) and phenobarbital (10-400 μg/ml) on basal and hormonally mediated resorption 5-day cultures of fetal rat forelimb rudiments. In this system both drugs significantly inhibited basal and PTH-stimulated 45Ca and [3H]hydroxyproline release, as well as 1,25-dihydroxyvitamin D3-stimulated 45Ca release. The effects of DPH and phenobarbital were additive, with DPH exhibiting a several-fold more potent inhibitory effect than phenobarbital. Whereas DPH exhibited a striking synergism with the inhibitory effects of human calcitonin (HCT) on PTH-induced resorption, the effect of phenobarbital was merely additive to that of HCT. PTH and PTH plus HCT-induced increases in bone cyclic AMP (cAMP) content were significantly inhibited by DPH but not by phenobarbital. However, in contrast to effects on 45Ca release, DPH inhibition of cAMP generation was not accentuated in the presence of HCT.