Phenobarbital urinary excretion

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

Barbiturates such as phenobarbital are weak acids. The toxicity of the barbiturate is mainly the result of the effects on the central nervous system. Only the nonionized form of the drug will distribute into the central nervous system. The proportion ionized will depend on the pKa and the pH of the blood. By increasing the pH of the blood using sodium bicarbonate administration to the poisoned patient, ionization of the barbiturate will be increased and distribution to tissues such as the brain will be decreased. Urinary excretion of the barbiturate will also be increased because the urinary pH will be increased. 

The inactive metabolites are excreted in the urine. The administration of bicarbonate enhances the urinary excretion of barbiturates that have a pK of 7.4 (phenobarbital and thiopental). This generalization is not true of other barbiturates. The long-term administration of barbiturates activates the cytochrome P-450 drug-metabolizing system. 

A variety of pathological changes of the liver occur with repeated exposures of rats, rabbits,guinea pigs and dogs to PCE. Hepatotoxicity is increased in rats pretreated with aroclor or phenobarbital. This observation as well as the urinary excretion of chlorinated metabolites points to the liver as a probable oxidation site (ref. 67). In man, acute intoxication has generally resulted from industrial degreasing operations. 

Acidifying the urine favors the reabsorption of weak acids, such as salicylates, and retards their excretion, whereas the reverse is true for weak bases. Alkafinization of the urine increases the excretion of weak acids. For example, it is possible to accelerate the excretion of phenobarbital (a weak acid) in an intoxicated patient by administration of sodium bicarbonate. On the other hand, the urinary excretion of weak bases is low in alkaline urine. 

The hepatic monooxygenase system is primarily responsible for oxidation of tetrachloroethylene. Thus, compounds that stimulate or induce tetrachloroethylene metabolism could influence the toxicity associated with exposure to this chemical. Results of experiments that have investigated possible enhancement of tetrachloroethylene-induced toxicity by increasing tetrachloroethylene metabolism have been equivocal. Pretreatment of rats with ethanol (Cornish and Adefrrin 1966 Klaassen and Plaa 1966) and phenobarbital (Cornish et al. 1973 Moslen et al. 1977) failed to enhance tetrachloroethylene hepatic toxicity. Pretreatment with polychlorinated biphenyls (PCBs), on the other hand, increased urinary excretion of tetrachloroethylene metabolites in rats and enhanced tetrachloroethylene-induced hepatotoxicity (Moslen etal. 1977). 

Severe osteomalacia developed in 2 women taking phenytoin or primidone and phenobarbital when they were given acetazolamide 750 mg daily, despite a normal intake of calcium. When the acetazolamide was withdrawn, the hyperchloraemic acidosis that had been seen in both patients abated and their high urinary excretion of calcium fell by 50%. Similar cases have been described in 3 children given acetazolamide, phenytoin and primidone, with phenobarbital and/or metharbital, who developed rickets. 

Urinary Excretion of Phenobarbital in a Neonate Having Withdrawal Symptoms... 

When 3-methylcholanthrene was injected into normal rats, the urinary excretion of ascorbic acid (an indicator of ascorbic acid synthesis) increased to a large amount with a concomitant increase in hepatic 4-nitrophenol UDPGT activity. However, this phenomenon was not observed in the Gunn rat. On the other hand, injection of phenobarbital into this rat caused a marked increase in urinary excretion of ascorbic acid accompanied by an increase in hepatic activity of another isozyme, chloramphenicol UDPGT. In this situation, this isozyme would have supported the synthesis of ascorbic acid. 

The administration of polychlorinated biphenyl (PCB) isomers increases hepatic tissue content of ascorbic acid as well as urinary excretion of ascorbic acid in the rat (Horio et al., 1986) and similarly increases the content of the major cytochrome P-450 enzymes induced by both phenobarbital and 3-methylcholanthrene (De-nomme et aL, 1983 Parkinson et ai, 1983). Guinea pigs fed an ascorbic acid-deficient diet have lower content of cytochrome P-450. A trend has been observed toward a higher cytochrome P-450 content with increasing dietary ascorbic acid, suggesting that ascorbic acid also influences drug metabolism (Peterson et al., 1983). 

In humans, administration of o,p -DDD [l,l-dichloro-2-(4-chlorophenyl)-2-(2-chlorophenyl) ethane], phenobarbital, diphenylhydantoin, or phenylbutazone causes a marked elevation in the urinary excretion of 6 )5-hydroxycortisol presumably by accelerating the metabolism of glucocorticoids. Accordingly, treatment of animals with phenobarbital stimulates the hydroxylation by hepatic microsomes of corticosterone, deoxycorticosterone, cortisone, and cortisol, whereas 3-methylcholanthrene has negligible effect on the hydroxylation of cortisone or cortisol. The physiological consequences of this induction, however, remain obscure. 

The answer is a. (Hardman, pp 16-20.) Sodium bicarbonate is excreted principally in the urine and alkalinizes it. Increasing urinary pH interferes with the passive renal tubular reabsorption of organic acids (such as aspirin and phenobarbital) by increasing the ionic form of the drug in the tubular filtrate. This would increase their excretion. Excretion of organic bases (such as amphetamine, cocaine, phencyclidine, and morphine) would be enhanced by acidifying the urine. 

Phenobarbital is a potent enzyme inducer and interacts with many drugs. The amount of phenobarbital excreted renally can be increased by giving diuretics and urinary atkalinizers. 

The tissue distributions of [l- C]- and [2,3- 4C]aciy lonitrile (40 mg/kg) were compared in Wistar rats after intraperitoneal and oral administration (Sapota, 1982). The relative distributions of the two labelled forms were very similar and the principal locations of C were erythrocytes, liver and kidney. After oral administration, the rate of elimination from tissues was slower for [cyano- C -than for [l,2-vz v/- 4C]acrylonitrile. After gavage administration of 46 mg/kg bw [2-i4C]acrylonitrile to Fischer 344 rats, radioactivity was well absorbed from the gastrointestinal tract and distributed to all major tissues 24 h after dosing. The highest levels were found in the forestomach, blood and urinary bladder. Prior treatment of rats with phenobarbital had little effect on the pattern of distribution and excretion of 4C, but the CYP inhibitor SKF-525A caused marked changes, with less excretion (less than 40% in urine in 24 h compared with over 60% in... 

Burka et al. (1994) examined the effect of treatment of rats with phenobarbital and SKF-525A on the urinary metabolite profile of [2- - C]aciy lonitnle. Phenobarbital treatment increased the excretion of products attributed to the oxidation of acrylonitrile to CEO, while SKF-525A treatment enhanced the excretion of the mercapturic acid derived from the glutathione conjugation of acrylonitrile itself. 

The effect of urinary pH on drug ionization also has toxicological implications. For example, in cases of phenobarbital (a weak acid barbiturate) overdose the urine can be alkalinized (the pH elevated) by administering sodium bicarbonate to the patient. The resultant increase in pH shifts the dissociation equilibrium for this weak acid to the right, producing an increase in the proportion of the ionized form, less reabsorption in the kidneys, and more rapid elimination. Conversely, acidifying the urine with ammonium chloride will increase the excretion rate of drugs that are weak bases since they will be more protonated (ionized) and less reabsorbed (more polar, less lipophilic). 

Drugs affecting fiver enzymes may alter phenobarbital metabolism, but phenobarbital clearance is not affected by fiver blood flow. The elimination of phenobarbital is linear. Because tubular reabsorption of phenobarbital is pH dependent, the amount excreted renally can be increased by giving diuretics and urinary alkalinizers." ... 

D. Enhancement of Elimination Enhancement of elimination is possible for a number of toxins, including manipulation of urine pH to accelerate renal excretion of weak acids and bases. For example, alkaline diuresis is effective in toxicity due to fluoride, isoniazid, fluoroquinolones, phenobarbital, and salicylates. Urinary acidiflcation may be useful in toxicity due to weak bases, including amphetamines, nicotine, and phencyclidine, but care must be taken to avoid acidosis and renal failure in rhabdomyolysis. Hemodialysis or hemoperfusion enhances the elimination of many toxic compounds, including acetaminophen, ethylene glycol, formaldehyde, lithium, methanol, procainamide, quinidine, salicylates, and theophylline. Cathartics such as sorbitol (70%) may decrease absorption and hasten removal of toxins from the gastrointestinal tract. 

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