Hepatotoxic and Hepatoprotective Potential of Histamine (H&Receptor Antagonists

MARTIN BLACK, M.D.

Phi/ade$hia, Pennsylvania

From the Department of Gastroenterology, Temple University School of Medicine, Philadelphia, Penn- sylvania. Requests for reprints should be ad- dressed to Dr. Martin Black, Professor of Pharma- cology and Medicine, Department of Gastroenter- ology, Temple University School of Medicine, 3401 N. Broad Street, Philadelphia, Pennsylvania 19140.

It has been increasingly recognized that the histamine (H&receptor antagonists are associated in rare instances with idiosyncratic hep- atotoxic reactions and with drug interactions related to their inhibi- tion of the hepatic cytochrome P-450 enzymes. What have not been appreciated until recently are the potential therapeutic benefits that may be derived from cytochrome P-450 inhibition. Evidence is pre- sented here that cytochrome P-450 inhibition may protect against hepatic damage induced by acetaminophen and other drugs metab- olized via this system. Acetaminophen hepatotoxicity is an espe- cially important problem because of the widespread use of this agent and the evidence that the potential for such injury may be increased in alcoholic persons. Cimetidine has been used in se- lected cases, one of which is described here, to treat acetamino- phen hepatotoxicity. All HZ-receptor antagonists may not be alike in this regard. Experimental studies in animal models indicate that al- though cimetidine protects against the hepatotoxic effects of acet- aminophen, ranitidine may actually potentiate hepatic damage. It is thought that the difference between these two HZ-receptor antago- nists may lie in their affinities for binding to the cytochrome P-450 enzymes. Cimetidine, which binds more strongly, inhibits this sys- tem more efficiently, whereas the inhibition produced by ranitidine is not sufficient to confer a protective effect against drug-induced hepatotoxicity.

Like many other therapeutic agents, the histamine (H&receptor antago- nists cimetidine and ranitidine have pharmacologic activities other than the one of prime therapeutic interest. The Hz-receptor antagonists have long been known to have some hepatic effects, but only recently has evidence come to light indicating that some of these effects may be bene- ficial and have possible therapeutic applications. The hepatotoxic and hepatoprotective effects of the Hz-receptor antagonists are reviewed here.

H,-RECEPTOR ANTAGONISTS AND THE LIVER

Idiosyncratic Hepatotoxicity. In rare instances, cimetidine and raniti- dine may cause idiosyncratic forms of hepatotoxicity. A comparison of the hepatic profiles of these two agents is shown in Table I. With cimetidine, the idiosyncratic reaction is almost always cholestatic. With ranitidine, the hepatotoxic reaction is occasionally cholestatic but, more typically, is cholangitic with accompanying fever and chills and occasional abdominal pain, simulating ascending cholangitis [I]. In a small number of cases, ranitidine-associated hepatotoxic reactions have been necroinflam- matory.

88 December 18, 1987 The American Journal of Medicine Volume 83 (suppl 8A)

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TABLE I Hepatic Effects: Comparison of Cimetidine and Flanitidine

Characteristic Cimetidine

Liver toxicity Clinical syndrome Cholestasis Frequency 1 in 300,000 to 600,000 Reversibility Rapid Outcome Recovery

Binds to cytochrome P-450 At relatively low concentrations

Drug interactions Common

Acetaminophen hepatotoxicity experimental Decreased production of toxic metabolite aspects

Clinical implications May be useful therapeutically

Ranitidine

Cholangitis 1 in 75,000 to 150,000’ Rapid Recovery

At high molar concentrations

Occasional

May decrease acetaminophen hepatotoxicity

May be dangerous to take compounds simultaneously

“Approximate frequencies based upon reported cases in first six months after Food and Drug Administration approval and total number of prescriptions written.

The incidence rates for such idiosyncratic hepatotoxic reactions are low for both cimetidine and ranitidine. Based on the frequency of reported cases in the first six months after Food and Drug Administration marketing approval, cimetidine hepatotoxicity occurs approximately once for every 300,000 to 600,000 prescriptions and ranitidine hepatotoxicity occurs once for every 75,000 to 150,000 prescriptions. These ratios suggest that hepatotoxicity. is more common with ranitidine than with cimetidine treat- ment [2], although such reactions are very rare with both drugs. The reactions are reversible upon discontinuation of drug therapy and there have been no reports of deaths connected to such reactions. Binding to Hepatic Cytochrome P-450 Enzymes. When cimetidine or ranitidine is added to liver micro- somes and examined by difference spectroscopy, the spectral curves obtained are typical of type II substrates [3,4]. Many type II substrates, which include such drugs as isoniazid, ketoconazole, and miconazole, have been shown to be inhibitors of the metabolism of type I sub- strates [5-71. The affinity of cimetidine, an imidazole com- pound, for binding with the hepatic cytochrome P-450 enzymes has been recognized since Pelkonen and Puurunen’s [3] original observations in 1980. Ranitidine also binds to these enzymes, but it does not bind as read- ily [4]. Such binding forms the biochemical basis for the drug-drug interactions observed between cimetidine or ranitidine and many drugs that are metabolized through the hepatic cytochrome P-450 system.

It is now becoming evident that many isoenzymes of cytochrome P-450 exist. Studies with rabbit liver have shown that at least nine different cytochrome P-450 iso- enzymes exist [8]. Different compounds induce the differ- ent isoenzymes, and the isoenzymes also differ in sub- strate specificity. Thus, when issues relating to drug ef- fects on the cytochrome P-450 system are discussed, it is necessary to identify the particular cytochrome P-450 iso-

December 18,1987

enzyme involved. For example, although cimetidine clearly does bind to cytochrome P-450 enzymes in both animal and human liver microsomes, it may not inhibit all isoenzymes. More information exists about specific cyto- chrome P-450 isoenzymes in animal models than in human liver, but ongoing investigations in our laboratory are exploring the role of various cytochrome P-450 isoen- zymes in human health and disease.

Much has been written about the potential for drug in- teractions via the cytochrome P-450 system, but there is now evidence that, in certain clinical settings, this interac- tion may be beneficial. The possible utilization of cyto- chrome P-450 inhibition by cimetidine in the treatment of acetaminophen toxicity is discussed next.

ACETAMINOPHEN TOXICITY: ROLE OF CIMETIDINE IN MANAGEMENT

Pathogenesis of Acetaminophen Toxicity. Acetami- nophen is a mild analgesic and antipyretic compound structurally related to acetanilid and phenacetin; all these compounds were synthesized in the late 1800s and have been used therapeutically since then. Phenacetin was the most popular of these agents in the early part of the 20th century, but its use began to decline about 25 years ago as it became obvious that it was associated with chronic renal toxicity. As phenacetin use declined, acetamino- phen increased in popularity. Although acetaminophen use was less often complicated by renal toxicity, it soon became evident that acetaminophen was a predictable hepatotoxin. For a predictable hepatotoxin, unlike a nonpredictable hepatotoxin, a clear dose-response rela- tionship exists, reproducible hepatic injury can be pro- duced in laboratory animal studies, the morphologic ex- pressions of injury are limited, and, finally, the mechanism of injury clearly involves biochemical phenomena. For a nonpredictable hepatotoxin, the dose-response relation- ship is not clear, injury is rarely reproducible in animal

The American Journal of Medicine Volume 83 (suppl 8A) 89

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2000 million tablets

t t 4 t t 1964 1965 1966 1967 1966 1969 1970 1971 1972 1973 1974

Figure 1. Timing and extent of publicity relating to paracetamol-induced deaths. Experience with acetaminophen (parac- etamol) hepatotoxicity in the United King- dom, 1964 to 1974. Reproduced with permission from [9].

NH.CO.CH, NH.CO.CH,

Acetaminophen (therapeutic dose)

3

0 OH

I

Microsomal mixed ( function oxidase system

1

i I

i N.CO.CH,

II

Postulated acetaminophen toxic metabolite 0 I I

(N-acetyl-pbenzoquinone imine. NAPQI) 11 0

+ Glucuronic acid or sulfate I

Glucuronide or sulfate

(lngntates)

Glutathione conjugation

l

NH.CO.CH,

Glutathione

OH

1 Mercapturic acid metabolites of acetaminophen

Figure 2. Pathways of acetaminophen metabolism following ingestion of therapeutic quantities of the drug in nonalcoholic persons. Adapted with permission from [75].

70 December l&l997 The American Journal of Mfdlcine Volume 93 (suppl6A)

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NH.CO.CH, NH.CO.CH,

Acetaminophen (massive dose)

OH

MicroBomal mixed function oxidase system

1 N.CO.CH,

II

Postulated acetaminophen toxic metabolite 0 I I

(N-acetyl-p-benzoquinone imine. NAPQI) 11

+ Glucuronic acid or sulfate

( r;;te;iates )

Glutathione conjugation

0 0 Glucuronide or sulfate

NH.CO.CH,

Glutathione

OH

1 Mercapturic acid metabolites of acetaminophen

Cell necrosis Electrophilic attack of nearby structures in hepatocyte

_ gufe 3. Pathways of acetaminophen metabolism following ingestion of massive quantities of the drug. Adapted with permis-

sion from [ 151.

studies, a broader spectrum of liver damage is found, and there is a continuing disagreement over mechanism of in- jury, with some authorities supporting biochemical bases while others suspect immunoallergic phenomena.

Acetaminophen hepatotoxicity occurs most characteris- tically, therefore, in patients who ingest large quantities of the medication, usually in a suicidal overdose. As acetam- inophen use has grown, the number of deaths caused by overdose has also increased dramatically, as shown in Figure 1 [9], which plots the rise in paracetamol (as acet- aminophen is known in the United Kingdom) sales against the number of deaths. It can be seen that by the 197Os, a virtual epidemic of paracetamol overdose had arisen. This phenomenon was attributed by one investigator to both the increased availability of paracetamol and to the exten- sive media coverage of paracetamol overdose [9].

In the early 197Os, intensive laboratory investigations by several groups of investigators established the meta- bolic basis for acetaminophen hepatotoxicity [IO-141. These studies demonstrated the critical involvement of the cytochrome P-450 system in the production of a toxic metabolite of acetaminophen, termed N-acetyl-p-benzo- quinoneimine. The proposed pathway for metabolism of therapeutic doses of acetaminophen is shown in Figure 2

[15]. Acetaminophen is extensively metabolized by the glucuronic acid or sulfate conjugation pathways. The con- jugation pathways normally account for 85 percent of the acetaminophen metabolites identified in urine after a ther- apeutic dose of acetaminophen. A small amount of acet- aminophen is normally metabolized via the microsomal mixed-function oxidase system, which involves cyto- chrome P-450 enzymes. This pathway generates the po- tential toxic metabolite named previously. Under normal conditions, this metabolite is detoxified via glutathione conjugation, producing mercapturic acid metabolites that are excreted in the urine. These metabolites usually ac- count for no more than five percent of all acetaminophen metabolites.

However, when massive doses of acetaminophen are taken, the pattern of metabolism changes, as shown in Figure 3 [15]. The glucuronidation conjugation pathways have a limited capacity, and more drug is metabolized by the mixed-function oxidase pathway. The toxic metabolite is therefore produced in greater amounts. Glutathione repletion of the hepatocyte is eventually overwhelmed, leading to an accumulation of the toxic metabolite, which engages in electrophilic attack on nearby structures in the hepatocyte. Cellular necrosis ensues.

December 18, 1987 The Amerlcen Journal of Medicine Volume 83 (suppl 6A) 71

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TABLE II Alcohol-Induced Acetaminophen Hepatotoxicity: Summary

l Twenty-five cases reported (1977-l 986) l Five fatalities reported (1977-1986) l Acetaminophen consumption (range)

All cases: 3.0-16.5 g per day Fatalities: 6-14 g per day

l Aspartate aminotransferase (range) All cases: 2,870-29,700 Ill/liter Fatalities: 3,561-19,750 IUiliter

l Total bilirubin (range) All cases: 3.5-68 mg/dl Fatalities: 8-68 mg/dl

Reproduced with permission from [14].

Potentiation of Acetaminophen Hepatotoxicity by Al- cohol. Clinical reports have indicated that alcohol can potentiate the hepatotoxic effects of acetaminophen. Twenty-five such cases were summarized recently in an article by Seeff and colleagues [16]. In these alcoholic patients, severe hepatotoxicity developed after ingestion of therapeutic doses of acetaminophen. The doses of acetaminophen were quite low: six patients took 4 g or less in a 24-hour period, an amount equivalent to only eight extra-strength tablets (500 mg). Some patients had severe liver injury marked by very high bilirubin levels and prolonged prothrombin times. Five patients died. The re- sults of this study are summarized in Table II.

These cases probably represent only a small proportion of the actual number. At least six cases have been ob- served over the past 10 years at Temple University Hospi- tal, one of which is described here. This case involved a 63-year-old male alcoholic patient who came to our hospi- tal with chronic obstructive pulmonary disease and vague musculoskeletal discomfort. The patient had been taking four to six extra-strength (500 mg) acetaminophen tablets daily for more than one year. Three days before he sought medical attention, his musculoskeletal symptoms in- creased and he raised his daily intake of acetaminophen to eight to 10 500-mg tablets daily, a total daily dose of 4 to 5 g. His initial complaints upon examination in the Emergency Room were shortness of breath and weak- ness. He was found to be hypoglycemic and to have met- abolic acidosis. Liver function studies showed a bilirubin level of 3.9 mg/dl, an aspartate aminotransferase concen- tration of 13,000 Ill/liter, an alanine aminotransferase level of 3,300 Ill/liter, and a lactate dehydrogenase level of nearly 6,000 Ill/liter. Acetaminophen could still be de- tected in the patient 10 and 31 hours after admission, demonstrating that the half-life for acetaminophen (nor- mally one to three hours) is markedly prolonged in the presence of severe, acute liver injury.

Acute hepatic injury from acetaminophen in alcoholic patients, such as that described above, may not represent the only type of acetaminophen-induced damage. It is quite probable that some patients experience many epi-

sodes of subclinical hepatic injury before seeking medical attention. Such injury might well contribute to the estab- lishment of chronic hepatitis and cirrhosis in alcoholic pa- tients. Thus, the potential role of acetaminophen in he- patic damage should be considered in alcoholic patients who consume acetaminophen on a continuing basis.

The phenomenon of alcohol potentiation of acetamino- phen hepatotoxicity is being explored in several laborato- ries, including my own [17]. Alcohol may potentiate acet- aminophen hepatotoxicity by inducing a particular isoen- zyme of cytochrome P-450. This particular form of cyto- chrome P-450 may generate the toxic metabolite of acet- aminophen. Thus, it is possible that alcohol may potenti- ate acetaminophen hepatotoxicity by increasing produc- tion of the toxic metabolite. However, other possibilities cannot yet be ruled out; it is possible that alcohol may affect the detoxification of the toxic metabolite either by a direct effect on glutathione synthesis or by starvation. Interaction of Hp-Receptor Antagonists with Hepatic Metabolism of Acetaminophen. Because production of the toxic metabolite involved in acetaminophen hepato- toxicity is related to the mixed-function oxidase system, interest in inhibitors of that system has been aroused.

Some investigators have shown that cimetidine ap- pears to protect against acetaminophen hepatotoxicity in experimental models [I 81. Cimetidine administration prior to, or shortly after, acetaminophen administration was shown to confer significant protection against hepatotox- icity in rats (Figure 4). In fact, when cimetidine was given prior to the acetaminophen dose, it was as effective as acetylcysteine, the current standard therapy for acetami- nophen overdose. The mechanism of protection is clearly related to cimetidine binding to the cytochrome P-450 enzymes, inhibiting this pathway and reducing formation of the toxic metabolite of acetaminophen.

In vitro studies in our laboratory, as yet unpublished, have shown that cimetidine reduces the formation of the toxic metabolite of acetaminophen in microsomal prepa- rations of untreated rabbit liver, ethanol-treated rabbit liver, and human liver. The effects of cimetidine on these three liver microsomal preparations were assessed with an in vitro assay system in which the cysteine conjugate of acetaminophen was measured as an index of generation of the toxic acetaminophen metabolite. These studies showed that ethanol pretreatment enhanced the formation of toxic acetaminophen metabolite by rabbit liver; human liver produced amounts of toxic metabolite comparable to ethanol-treated rabbit liver. Addition of 0.2 mM cimetidine reduced the rate of toxic metabolite formation in all three preparations, decreasing it by approximately 50 percent in human liver.

Several studies have indicated that ranitidine may not share the protective properties of cimetidine against acet- aminophen-induced hepatotoxicity. Leonard and co- workers [I91 evaluated the hepatotoxicity of single doses of acetaminophen in rats pretreated with several doses of

72 December 18, 1967 The American Journal of Medicine Volume 63 (suppl 6A)

SYMPOSIUM ON l-l~-RECEPTOR ANTAGONIST THERAPY--BLACK

8000 l p co.02 v) .= 5 6000 **p <0.0001

b3 6 4000 * iz

2000 ** Acetaminophen -t Cimetidine

only 4 h post + Cimetidine

1 h pre + N-ac-cys

4 h post + N-ac-cys

1 h pre

Figure 4. Effects of cimetidine and N-acetylcysteine (N-ac-cys) (given one hour before or four hours after) on hepatotoxicity (serum glutamic oxaloacetic transaminase [SGOT] levels) following a single intraperitoneal administration of acetaminophen (500 mglkg) in rats. Reproduced with permission from [18].

ranitidine (10 to 150 mg/kg) as measured by serum ala- against such injury. N-Acetylcysteine may lead to in- nine transaminase activity. Rats treated with 25 and 50 creased formation of glutathione or it may bind directly mg/kg of ranitidine had significantly higher serum alanine with the toxic metabolite. Whatever the mechanism, this transaminase activity than did control rats; a protective agent inactivates the toxic metabolite of acetaminophen effect against hepatic damage was manifest only at 150 and thereby serves as an antidote to acetaminophen mg/kg, the highest dose level (Figure 5). overdose [ 151.

In another series of experiments, the severity of histo- logic liver injury following ranitidine pretreatment and ac- etaminophen was assessed [15] (Figure 6). Histologic scores were worse for rats pretreated with a low dose of ranitidine (50 mg/kg) than for control rats for three of the acetaminophen doses. Thus, it appears that ranitidine potentiates the hepatotoxicity of acetaminophen in rats.

Other findings indicating differences between cimeti- dine and ranitidine come from a study of the inhibition of acetaminophen glucuronidation by a number of Hz-recep- tor antagonists [20]. This study showed that these agents varied in the degree of inhibition produced. Oxmetidine, an Hz-receptor antagonist that has never been marketed, was found to be the most potent inhibitor of glucuronida- tion, followed by ranitidine. Cimetidine was five times less potent than ranitidine in the inhibition of acetaminophen glucuronidation. Oxmetidine not only inhibited formation of the glucuronide conjugate of acetaminophen but also increased the formation of the conjugate formed by the acetaminophen toxic metabolite.

The possibility that cimetidine might have a therapeutic role in management of acute acetaminophen overdose has been raised by the group at Vanderbilt University headed by Dr. Steven Schenker, who performed the ani- mal experiments described previously on protective ef- fects of cimetidine and acetylcysteine [18]. These results were confirmed in later animal investigations by the same group [21]. However, no clinical studies have been con- ducted to evaluate the usefulness of cimetidine in acet-

The clinical relevance of these laboratory studies is unknown at present. There have been occasional case reports of hepatotoxicity in individuals taking acetamino- phen and ranitidine together, but most instances have represented idiosyncratic reactions to ranitidine rather than ranitidine potentiation of acetaminophen hepatotox- icity.

APAP + 10 + 25 + 50 +100 + 150 Ranitidine Ranitidine Treatment (W~cJ) hi/kg)

TREATMENT OF ACETAMINOPHEN HEPATOTOXICITY

Awareness of the critical role of glutathione in acetamino- phen-induced hepatotoxicity led to the identification of a compound, N-acetylcysteine, that offers protection

Figure 5. tftects of several ranitidine pretreatment regi- mens on hepatotoxicity (serum alanine transaminase [ALT] activity) following a single intragastric administration (750 mgfkg) of acetaminophen (APAP) in rats. Reproduced with permission from [19].

December 18, 1987 The American Journal of Medicine Volume 83 (suppl 8A) 73

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NH.CO,CH,

Acetaminophen

Microsomal mixed function oxidase system

+ Glucuronic acid or sulfate

NH.CO.CH,

II Glutathione

Postulated acetaminophen 1 toxic metabolite 0 1

(N-acetyl-imidoquinone) l-l

Cell necrosis Electrophilic attack of nearby structures in hepatocyte

conjugation

t

Diethylmaleate 1 Starvation (?) Alcohol

I I

NH.CO.CH,

3 0 Glucuronide or sulfate

NH.CO.CH,

OH

1 Mercapturic acid metabolites of acetaminophen

igure 6. Pathways of acetaminophen metabolism indicating possible effects of ranitidine pretreatment in rats. Adapted with permission from [15).

aminophen overdose. Cimetidine would seem, neverthe- less, to offer an additional line of therapy for acetamino- phen overdose that ought not to impair the evident bene- fits of acetylcysteine administration.

In fact, we have some limited experience in using cimet- idine in this setting. In the case of acetaminophen hepato- toxicity described earlier in this paper, we had occasion to use a novel therapeutic intervention, in this case involving cimetidine. Because of the persistence of significant amounts of acetaminophen in the blood 31 hours after admission, hemodialysis was contemplated to remove the remaining drug. Instead, it was decided to initiate intrave- nous administration of cimetidine for two reasons. First, prevention of generation of additional quantities of the toxic metabolite from the remaining acetaminophen was desirable. Second, suppression of gastric acid secretion was desirable to avoid gastrointestinal hemorrhage in a patient with a prolonged prothrombin time. This complica- tion had been the cause of death in another alcoholic pa- tient with acetaminophen hepatotoxicity treated previously at our institution [22]. A relatively high dose of cimetidine (300 mg every three hours), given as an intravenous infu-

74 December 18, 1987 The American Journal of Medicine Volume 83 (suppl 6A)

sion, was used to ensure the maintenance of inhibition of the cytochrome P-450 system. A number of doses of ace- tylcysteine were also given, but this therapy was discon- tinued soon after because the patient was intolerant to it. To our surprise, there was a prompt improvement in the prothrombin time, which returned to normal levels within hours of initiation of therapy. Results of other laboratory function tests also improved. Within one week, a liver bi- opsy was performed and results indicated the typical fea- tures of acute acetaminophen liver injury. Such a case report does not prove that the recovery of the patient can be attributed to cimetidine therapy; a randomized clinical trial of cimetidine treatment of acetaminophen overdose is currently contemplated, however.

OTHER DRUG-INDUCED HEPATOTOXICITIES

Other types of drug-induced hepatic injury may also be susceptible to manipulation of the cytochrome P-450 en- zymes. There is increasing evidence that hepatic injury induced by halothane may be mediated through the mixed-function oxidase pathway. The mechanism of halo- thane hepatotoxicity has long been a subject of dispute.

SYMPOSIUM ON Hz-RECEPTOR ANTAGONIST THERAPY-BLACK

Some regard it as the classic example of an immunologi- cally mediated injury [23]. However, an experimental model of halothane hepatotoxicity has been described and fairly well characterized. Furthermore, studies have suggested that halothane is metabolized by the mixed- function oxidase system in rats to an active, halogenated metabolite, which can produce centrizonal necrosis [24].

Some recent clinical observations, reported by a Japa- nese group, suggest the involvement of the cytochrome P-450 system in halothane-associated hepatotoxicity [25]. In their study, observations were made on 279 surgical patients who received halothane anesthesia. One hun- dred patients had received phenobarbital prior to adminis- tration of anesthesia in doses ranging from 80 to 120 mg daily for 4 to 40 days. The other 179 patients did not re- ceive phenobarbital. The demographic characteristics of the two groups were comparable, as was duration of sur- gery. However, within the phenobarbital-treated group, halothane-associated hepatic injury developed in seven patients (7 percent), whereas only one (0.5 percent) of the non-phenobarbital-treated patients had hepatic damage, demonstrating a significant difference (p CO.01). These observations suggest that phenobarbital, which is known

to induce certain cytochrome P-450 isoenzymes, may potentiate halothane hepatic injury. It is possible that cyto- chrome P-450 inhibitors, such as cimetidine, might be able to protect against such damage.

COMMENTS

If toxic metabolites produced via the cytochrome P-450 system are involved in drug-induced hepatotoxicities, cer- tain clinical implications may be drawn. First, it would be prudent to avoid the use of potentially hepatotoxic drugs in susceptible persons when those persons can be identi- fied. Thus, acetaminophen should not be recommended for alcoholic patients. Second, it would be wise to avoid the use of drug combinations that lead to enhanced for- mation of toxic metabolites. Halothane and phenobarbital appear to enhance formation of toxic halothane metabo- lites; acetaminophen and ranitidine may have a similar synergistic effect on the production of the toxic acetami- nophen metabolite. When susceptible persons must take potentially hepatotoxic drugs or when hepatotoxic drug combinations must be given, consideration may be given to use of a cytochrome P-450 inhibitor, such as cimeti- dine, as a prophylactic agent.

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