High performance liquid chromatographic determination of thalidomide in patients affected by hepatocellular carcinoma
Giuseppe SaccomanniV. TuriniClementina ManeraGiorgio PlacanicaEmanuela Omodeo SalèCostantino JemosMario GiorgiMarco Macchia
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Phenacetin
To investigate the pathogenesis of phenacetin-induced nephropathy, the influence of aspirin and caffeine on phenacetin metabolism was studied. Eight healthy male volunteers participated in the study after giving written consent. They were randomly divided into 2 groups. Phenacetin was given to one group, and phenacetin, aspirin and caffeine were given to the other group based on a cross-over design. Blood and urine were collected over a period of 24 hours. The urinary excretion and plasma concentrations of unchanged phenacetin, acetaminophen, acetaminophen glucuronide and acetaminophen sulphate were measured by high performance liquid chromatography. The proportions of urinary excretion of these substances were not significantly different in the two groups. The pharmacokinetic parameters of these substances were also fundamentally identical. It may be concluded that aspirin and caffeine do not alter the phenacetin metabolism. However, other minor metabolites such as p-phenetidine must be closely investigated before we can draw any final conclusions.
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Nine nonsmokers and nine individuals who smoked more than 15 Cigarettes per day were administered 900 mg of phenacetin orally, and the concentration of phenacetin in plasma was measured 1, 2, 3.5, and 5 hours after the dose. The plasma levels of phenacetin in the smokers were markedly lower than in the nonsmokers. The plasma levels of unconiugated or total N‐acetyl‐p‐aminophenol in the smokers were the same or only slightly lower than in the nonsmokers, and the ratios of the plasma concentration of total N‐acetyl‐p‐aminophenol to phenacetin were increased severalfold in the smokers. These results indicated that cigarette smoking stimulated the metabolism of phenacetin. To learn whether polycyclic hydrocarbons in cigarette smoke could influence the gastrointestinal metaboli5m of phenacetin, we studied the effects of 3,4‐benzpyrene administration on the metabolism of CILphenacetin by enzymes in the intestinal mucosa of the rat. The data indicated that O‐dealkylation of phenacetin did occur—to a small extent—by an enzyme system in the small intestine, and that the activity of this enzyme system was stimulated by treatment of rats with 3,4‐benzpyrene.
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Although there are some reports which state that phenacetin is unlikely to be theprimary causative agent in analgesic nephropathy (Prescott, 1982), 80% of the 285phenacetin abusers observed in our clinic between 1962 and 1979 were suffering fromchronic interstitial nephritis (Nitzsche et al., 1980). In order to ascertain whether phenacetin itself or one of its metabolites is responsible for this nephritis we have comparedthe pharmacokinetics and metabolic profile of phenacetin in 2 groups of phenacetinabusers with and without nephritis.Phenacetin (900 mg), contained in gelatin capsules, was administered orally after anovernight fast. Blood and urine samples were collected. Plasma and urine concentrations of unchanged phenacetin and its major metabolites were determined by HPLCwith spectrophotometric detection (254 nm).Urinary elimination of phenacetin and metabolites was quantified as the total amount (percentage of dose) in 24 h.The results suggest that the cause of nephritis in susceptible phenacetin abusers isnot associated with altered elimination of either phenacetin itself or the metabolitesmeasured in this study.
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The mechanisms underlying phenacetin-induced toxicity and carcinogenicity are not clear. In particular, it is not known whether these effects are mediated by metabolic activation of the drug. CYP1A2 is known to metabolize phenacetin in vitro. To determine the role of this enzyme in vivo, the toxicity and carcinogenicity of phenacetin was examined in Cyp1a2-null mice (that lack CYP1A2). Six- to 8-week-old wild type (+/+) or null (-/-) mice were fed either a control diet, or one containing 1.25% phenacetin, ad libitum for up to 67 weeks. Representative groups of mice were examined for phenacetin-induced toxicity and carcinogenicity after 36, 48, 58, or 67 weeks of feeding. Consistent with the known role of CYP1A2 in phenacetin metabolism, plasma levels of phenacetin were higher and acetaminophen levels lower in the (-/-) mice fed phenacetin compared to phenacetin-fed (+/+) controls. Weight gain was significantly depressed in both groups of phenacetin-fed mice after 4 weeks of feeding, and continued to be lower for the remainder of the experiment, compared to controls. Hepatomegaly and splenomegaly were more severe in (-/-) mice but present in both genotypes fed phenacetin at all time points assessed. Histological analysis of liver, kidney, spleen, and urogenital tract also revealed a differential response in the (-/-) mice fed phenacetin compared to (+/+) mice fed the same diet. Further, mortality was the most severe in the (-/-) mice fed phenacetin than in all other groups. Despite significant toxicity in (-/-) mice fed phenacetin, only one renal carcinoma was found among them. Results from this work demonstrate that, in the absence of CYP1A2, phenacetin is more toxic than in controls. This provides evidence that metabolism of phenacetin by CYP1A2 alters toxicity in vivo, and suggests that alternate CYP1A2-independent metabolic pathways contribute to its toxicity.
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The effects of cigarette smoking on phenacetin metabolism in the rat and in man have been investigated. Exposure of rats to cigarette smoke or pretreatment with the polycyclic hydrocarbon, 3,4-benzpyrene (benzo[a]pyrene), resulted in a more rapid disappearance of phenacetin in vivo. Additional studies demonstrated that hydrocarbon and smoking pretreatment of rats enhanced the 0-dealkylation of phenacetin to N-acetyl-p-aminophenol (APAP) by the intestinal mucosa. Cigarette smoking also increased the metabolism of phenacetin in man. The plasma concentration of phenacetin in cigarette smokers was lower than that in nonsmokers, whereas the ratio of the concentration of APAP to that of phenacetin was increased severalfold in the smokers. No difference in plasma half-life of elimination of phenacetin or in the amount of APAP excreted was found between smokers and nonsmokers. The lower blood levels of phenacetin in cigarette smokers could be the result of increased intestinal metabolism of the drug and/or first-pass metabolism in the liver.
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Abstract Six groups of male Sprague‐Dawley rats were treated with phenacetin, phenazone or caffeine in the diet or with combinations of these chemicals. Another group received paracetamol in the diet and a further group received only the control diet. The rats were treated for up to 117 weeks. Renal pelvic tumors were only seen in rats treated with phenacetin or phenazone alone or in combination with caffeine, phenazone having slightly greater activity toward the urinary tract than phenacetin. Phenacetin, however, had a greater overall carcinogenic effect, inducing 31 malignant tumors. The urinary tract and the kidneys had the highest incidence of tumor followed by squamous‐cell carcinomas of the head and neck. Half of the rats treated with phenacetin, phenazone and caffeine in combination developed hepatomas. The explanation may be that the addition of phenazone and caffeine altered the metabolism of phenacetin, increasing the production of N ‐hydroxy‐phenacetin, a known liver carcinogen. The justification of using phenacetin as a human analgesic must be seriously questioned, and further studies with phenazone are required.
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