Effect of Experimental Hepatic Injury on the Clearance of Phenobarbital and Paraldehyde

Phenobarbital and paraldehyde are often used in patients with severe hepatic disease and delirium, although there are only few data on the clearance of these drugs by the damaged liver. We examined the clearance of these agents from blood in rats with liver injury induced by graded doses of carbon tetrachloride (CCl₄) and common bile duct ligation of 24 and 72 hr. Progressive hepatic injury was documented by light microscopy and liver function tests. Paraldehyde was assayed enzymatically and phenobarbital by spectrophotometry. The specificity of the phenobarbital assay for the parent drug was confirmed by countercurrent analysis. Phenobarbital clearance from blood after CCl₄ was prolonged. The t 1/2 in normal rats was 18 hr and in animals given 0.3, 0.6, 1.2, and 2.5 ml of CCl₄ per kg it was 29.6, 31.7, 40.4, and 35.2 hr, respectively (P < 0.05). The phenobarbital t 1/2 with varied doses of CCl₄ is not statistically different (P 〉 0.05). In nephrectomized animals, CCl₄ also prolonged the phenobarbital t In perfused livers taken from normal rats and from those given 0.15 and 0.3 ml of CCl₄ per kg, phenobarbital t 1/2, was 2.43, 5.45, and 8.48 hr, respectively (P < 0.05). These latter two studies indicate that CCl₄ prolongs phenobarbital clearance by a direct toxic effect on the liver, not the kidney. Bile duct ligation did not enhance phenobarbital retention. Carbon tetrachloride, even in doses of 0.1 ml per kg, markedly prolonged paraldehyde removal from blood (P < 0.001). Larger doses of CCl₄ (0.6 and 1.25 ml per kg) delayed even more paraldehyde clearance (P < 0.01). Bile duct ligation also caused paraldehyde accumulation in blood (P < 0.01). Thus, CC14-induced hepatic injury in rats delayed paraldehyde and phenobarbital clearance, and bile duct ligation caused paraldehyde accumulation in blood. These data suggest that these drugs should be used with caution in patients with hepatic damage.