Phenobarbital nephrotoxicity

Several animal studies indicate that chloroform interacts with other chemicals within the organism. The lethal and hepatotoxic effects of chloroform were increased by dicophane (DDT) (McLean 1970) and phenobarbital (a long-acting barbiturate) in rats (Ekstrom et al. 1988 McLean 1970 Scholler 1970). Increased hepatotoxic and nephrotoxic effects were observed after interaction with ketonic solvents and ketonic chemicals in rats (Hewitt and Brown 1984 Hewitt et al. 1990) and in mice (Cianflone et al. 1980 Hewitt et al. 1979). The hepatotoxicity of chloroform was also enhanced by co-exposure to carbon tetrachloride in rats (Harris et al. 1982) and by co-exposure to ethanol in mice (Kutob and Plaa 1962). Furthermore, ethanol pretreatment in rats enhanced chloroform-induced hepatotoxicity (Wang et al. 1994) and increased the in vitro metabolism of chloroform (Sato et al. 1981). 

Ahmadizadeh M, Kuo C, Echt R, et al. 1984. Effect of polybrominated biphenyls, b-naphthoflavone and phenobarbital on arylhydrocarbon hydroxylase activities and chloroform-induced nephrotoxicity and hepatotoxicity in male C57BL/6J and DBA/2J mice. Toxicology 31 343-352. 

Bailie MB, Smith JH, Newton JF, et al. 1984. Mechanism of chloroform nephrotoxicity. IV. Phenobarbital potentiation of in vitro chloroform metabolism and toxicity in rabbit kidneys. Toxicol Appl Pharmacol 74 285-292. 

Drugs that may affect tacrolimus include nephrotoxic agents (aminoglycosides, amphotericin B, cisplatin, cyclosporine), antifungals, bromocriptine, calcium channel blockers, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, methylprednisolone, metoclopramide, carbamazepine, phenobarbital, phenytoin, rifamycins, cisapride, chloramphenicol, metronidazole, nefazodone, omeprazole, protease inhibitors, macrolide antibiotics, fosphenytoin, and St. John s wort. 

Special attention is needed when new medications are prescribed to CSA-treated patients. CSA is extensively metabolized by the cytochrome P450 hver microsomal enzyme system [2, 3], and consequently drugs that interfere with this pathway can cause important changes in CSA blood levels (Table 3). Compounds inhibiting P450 enzymes, such as ketoconazole, erythromycin, verapamil, and diltiazem increase concentration of parent CSA and may cause acute nephrotoxicity. On the other hand, drugs that increase P450 enzyme activity, such as phenobarbital, carbamazepine and... 

Fowler BA, Fueler GW, Mushak P. Phenobarbital protection against methylmercury nephrotoxicity. Proc Soc Exp Biol Med 1975 149 75-9. 

Nephrotoxicity may be prevented or diminished by prehydration with 21 of normal saline administered over a 6-8 h period, followed by continued hydration during and after the cisplatin infusion. Nausea and vomiting may be managed with antiemetics. Electrolyte concentration should be monitored and supplemented as needed. Treatment for an anaphylactic reaction would include antihistamines, administered with or without epinephrine. If accidental exposure to the eyes or skin occurs, the affected skin area should be washed thoroughly with soap and water, and eyes should be flushed with copious amounts of tepid water for at least 15 min. Seizures should be treated with diazepam, lorazepan, phenobarbital, or phenytoin. 

The mechanism is believed to involve metabolic activation in the kidney itself. Thus, when radiolabelled chloroform was given to mice, in the kidney the radiolabel was localized in the tubular cells which were necrotic. Certain microsomal enzyme inducers such as 3-methylcholanthrene decreased the nephrotoxicity but not hepatotoxicity of chloroform, and phenobarbital pretreatment had no effect on nephrotoxicity but increased hepatotoxicity. Pretreatment with polybrominated biphenyls, however, increased toxicity to both target organs and also increased mixed function oxidase activity in both. In vitro studies have shown that microsomal enzymemediated metabolism of chloroform to C02 occurs in... 

B. To produce urinary aikaiinization, to enhance elimination of certain acidic drugs (salicylate, phenobarbital, chlorpropamide, chiorophenoxy herbicides-2,4-D), and to prevent nephrotoxicity from the renal deposition of myoglobin after severe rhabdomyoiysis or precipitation of methotrexate. (While enhanced elimination may be achieved, it is uncertain if clinical outcomes are improved with this therapy.) Also recommended by REAC/TS for internal contamination of uranium from radiation emergencies to prevent acute tubular necrosis (see Radiation, p 327). 

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