Cadmium potentiation of drug response—Role of the liver☆

Abstract Three days after a single cadmium dose (2 mg/kg), the duration of response to subsequently administered hexobarbital or zoxazolamine was potentiated. Duration of sleep was prolonged (225 per cent) in cadmium-treated rats, but the awakening plasma hexobarbital levels were similar in both the cadmium-treated animals and saline-treated controls. Moreover, cadmium-treated animals exhibited significantly higher plasma hexoharbital levels when sacrificed prior to awakening at a time corresponding to the mean duration of sleep in control rats, thus suggesting that the cadmium effect may be mediated by a decline in the plasma disappearance of hexobarbital. Duration of hexobarbital sleep was not changed in cadmium-treated hepatectomized rats compared to hepatectomized control animals, indicating the necessity of an intact liver for the cadmium effect to be elicited. In addition, pretreatment with cadmium significantly inhibited metabolism of hexobarbital in vitro in the isolated perfused rat liver (65 per cent). After the cadmium treatment zoxazolamine-induced paralysis was prolonged (185 per cent), but the plasma drug levels measured upon recovery were significantly lower. Significantly higher plasma levels of zoxazolamine were found in cadmium-treated rats when they were sacrificed prior to recovery at a time corresponding to the mean duration of paralysis in control rats. These results thus infer that the cadmium interaction with zoxazolamine may involve both an alteration in drug disposition as well as a change in tissue responsiveness.