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The results of previous studies which employed indirect techniques suggested that tetracycline induced a fatty liver in rats by inhibition of the hepatic secretion of triglyceride. The present study examines this concept directly by observation of the effect of tetracycline hydrochloride (100 mg/kg) given in vivo on the subsequently isolated perfused rat liver. This dose of tetracycline produced a 67% increase in hepatic triglyceride content in 3 h in vivo. The secretion of triglyceride by livers removed at 3 h from such animals and perfused in vitro was diminished in comparison with livers from control rats (1.6 μmoles/g per 4 h vs 3.4 μmoles/g per 4 h, P

Two patients are reported who developed hepatic disease with predominant intrahepatic cholestasis as a result of therapy directed at rheumatoid arthritis. In the 1st patient, the obstructive jaundice could reasonably be ascribed to gold therapy alone, whereas in the second individual either gold or phenylbutazone were implicated. Both patients had protracted and severe hepatic dysfunction. This rare reaction to these agents must be considered in the differential diagnosis of obstructive jaundice in patients with rheumatoid arthritis receiving this therapy.

The inhibition of urinary alkaline phosphatase has been shown to be caused principally by the inorganic phosphates which are naturally excreted in urine. An inorganic phosphate concentration of 15 mg./100 ml. resulted in approximately 50% inhibition, and that of 120 mg./100 ml. in an inhibition of about 90%. Evidence is presented which shows that the inhibition is of the competitive type.

SummarySince prior studies of the effect of alcohol on hepatic coenzyme A (CoA) and acetyl-CoA concentrations have yielded conflicting data, this investigation aimed to assess in detail the acute effect of alcohol on the concentration of these substances in liver. Rats and mice were given various loads of alcohol and, at selected time intervals, hepatic CoA and Acetyl CoA concentrations were determined and correlated with blood alcohol levels.The present study clearly shows that alcohol given acutely does not alter significantly hepatic CoA content and results in a normal or somewhat increased acetyl-CoA concentration in the liver. Acetaldehyde likewise failed to influence significantly the hepatic CoA concentration. We conclude that the acute depressive effect of alcohol on the hepatic citric acid cycle is not exerted at the CoA-acetyl-CoA level.

Changes in pH have been found to alter the toxicity of ammonia. Most of the studies have been performed with fixed acid or base, but the use of CO2 has recently attracted attention. Theoretically, however, these two methods of altering pH may not have similar effects. Fixed acid or base will penetrate tissue barriers poorly, thus causing an alteration in extracellular fluid-intracellular fluid pH gradient and a change in ammonia distribution. The alteration of pH gradient on inhalation of CO2 is usually of a much smaller degree, as the gas crosses membranes with ease. Consequently, the redistribution of ammonia will tend to be less marked. A comparison was made, therefore, between the effect on ammonia toxicity of equivalent plasma pH changes produced by both methods. The greater the reduction of blood pH with HCl infusion the greater the degree of protection afforded to mice against ammonium bicarbonate toxicity. Similar changes in pH produced by CO2 inhalation either had no effect or exacerbated ammonia toxicity. Concomitantly, HCl caused a marked diminution in the passage of a test dose of ammonia into the brain whereas CO2 had little or no effect.

Inasmuch as there are no quantitative data as to adenosine triphosphate (ATP) concentration in fetal and neonatal liver, a method for estimating the nucleotide in developing animals was devised and validated and the results obtained are reported here. The hepatic ATP levels, means ± sd, of fetal, one-day-old, nonpregnant adult, and pregnant guinea pigs were, respectively, 19.25 ± 3.36, 24.67 ± 3.90, 23.83 ± 2.98, and 26.12 ± 4.05 µmoles/g liver protein. In comparable groups of rats, which mature less rapidly, the values for ATP were 28.40 ± 3.24, 30.24 ± 2.72, 23.34 ± 2.17, and 22.62 ± 3.24 µmoles/g liver protein. It is concluded that 1) hepatic ATP concentration is specific for a species and does not appear to correlate primarily with its maturity, and 2) the levels of ATP in fetal and neonatal guinea pigs and rats are sufficiently similar to those in adult animals as not to be likely rate-limiting factors for hepatic ATP-dependent metabolic processes.

SummaryThe primary purpose of this study was to assess the hypothesis that a depletion of cerebral acetylcholine (ACh) may be responsible for the coma induced with ammonia. An ancillary aim was to determine the effect of ammonia on cerebral levels of two other likely neurotransmitters, serotonin and norepinephrine. Acetylcholine, serotonin, and norepinephrine were measured in the brain of rats with NH4Ac-induced stupor and in asympotomatic NaAc-injected and uninjected controls. Studies were carried out during and after the development of stupor; and both cortex and brainstem were assayed separately since these areas are believed to be primarily responsible for the maintenance of consciousness. Acetylcholine was measured by a specific and accurate fluorometric procedure. In rats with ammonia-induced precoma and coma, the ACh and norepinephrine levels in the cerebral cortex and brainstem were comparable to values seen in control animals. Cerebral serotonin likewise was normal during the development of stupo...

This report describes the clinical course of a patient with recurrent febrile episodes, associated with elevated plasma unconjugated etiocholanolone during fever andnormal hormone levels during asymptomatic intervals. In addition, the patient had noncaseating granulomatous liver infiltrates and myopathy. The patient's ability to conjugate and excrete etiocholanolone, menthol and cortisol was investigated. On 2 occasions (shortly after spontaneous febrile attacks) when fever was suppressed by dexamethasone therapy and once when the patient was afebrile and not on steroids, 25 mg of etiocholanolone was given intramuscularly in oil. A large proportion of the etiocholanolone was excreted during the ensuing 24 hr, totaling 33, 72 and 56%, respectively, of the administered dose. Of the total recovered, 75, 85 and 66% were extracted after β-glucuronidase hydrolysis and the remainder after hydrolysis of sulfates by acidification and continuous ether extraction. Only traces of unconjugated etiocholanolone were exc...

Ammonia toxicity was strikingly potentiated by short periods of hypoxia. The toxicity (ld50) of ammonium chloride administered intravenously to mice after 2 minutes in 15% oxygen was the same as that in 21% oxygen. However, its toxicity began to increase when they were exposed to 13% oxygen, and was markedly enhanced by each 2% decrement in oxygen concentration. The effect of a maximal lethal dose in 7% oxygen could be completely reversed in a matter of seconds by transferring the mice to 21% oxygen. Ninety-nine per cent oxygen did not alter the ld50, but significantly prolonged life. Hypoxia had a relatively slight effect on Metrazol toxicity. Blood pH was unchanged by the short periods of hypoxia prior to ammonia injection. Furthermore, measurements of brain ammonia concentrations following a standard dose of ammonium chloride at 21, 11 and 7% oxygen revealed that hypoxia had no effect on ammonia uptake or detoxication by the brain. It appeared therefore, that hypoxia directly potentiated the toxic effect of ammonia on the brain.

Plasma binding of chlordiazepoxide, diazepam, loraxepam, and oxazepam was determined by equilibrium dialysis in 20 male, healthy volunteers, 25-86 years old. A wide range of binding was observed, with the free fraction varying twofold for lorazepam, fourfold for chlordiazepoxide and diazepam, and over 20-fold for oxazepam. Statistically significant linear relationships were not observed between the degree of binding and age, serum albumin, or total protein for any of the drugs. There was, however, a correlation between the extent of binding for the four drugs. Because of the importance of unbound benzodiazepine levels in eliciting any pharmacological response and also in disposition, consideration of the wide interindividual variability in plasma binding must be made in interpreting pharmacodynamic and pharmacokinetic data.

SummaryBiliary excretion of injected unconjugated and conjugated C14-bilirubin was compared in one-day-old and in adult guinea pigs. In relation to adult animals, in the newborn elimination of unconjugated pigment was reduced by more than half and that of conjugated pigment, by one-third. This indicated that in addition to impaired conjugation, the liver of newborn animals exhibits an excretory defect, but the former represents the rate-limiting step in overall pigment metabolism.

1 The effect of intravenous administration of 100 units of heparin on plasma of diazepam, chlordiazepoxide, oxazepam and lorazepam was examined in fourteen normal subjects and five patients with cirrhosis. 2 In normal non-fasted subjects heparin caused a rapid 150--250% rise in the free fraction of diazepam, chlordiazepoxide and oxazepam but no change of lorazepam. The changes in free fraction were slightly smaller, but still significant, when the subjects were fasted. 3 These change in free fraction occurred within 90 s of administration of heparin and binding had returned to baseline by 30 to 45 min. 4 In the cirrhotic subjects the response to heparin was variable. 5 The use of heparin during drug disposition studies may affect the estimation of pharmacokinetic parameters and possibly pharmacological effects which are dependent on the circulating unbound drug level.

This study assessed the effect of alcoholic cirrhosis in man and of experimental liver injury in rats on the disposition and elimination of clindamycin. In 7 cirrhotics a statistically significant, although modest, prolongation of clindamycin half-life (T1/2beta) was observed as compared to values in 7 age-matched normal contrals (mean plus or minus SD: 4.46 plus or minus 0.93 hr vs 3.42 plus or minus 0.45 hr, P equals 0.02). This was primarily due to a decrease in clindamycin serum clearance in the cirrhotics, since the volume of distribution of the drug was similar in both groups (P more than 0.05). Serum protein binding of clindamycin was of the order of 79% and was comparable in both groups (P more than 0.05). There was a significant correlation between the T1/2beta of the drug and both total serum bilirubin and SGOT. The T1/2beta of clindamycin was also prolonged in rats with acute hepatic necrosis induced by administration of carbon tetrachloride and those with acute cholestasis caused by common bile duct ligation. These data suggest that liver damage, both chronic and acute, impairs the elimination of clindamycin but that this effect is small.

Liver disease in man is associated with a variety of pathophysiological processes which may influence the disposition of drugs in several ways. Interpretation of the observed pharmacokinetic changes in liver disease requires an understanding of the relationship between systemic drug clearance (Cls), volume of distribution (Vd) and the elimination half-life [t1/2(beta)], i.e. t1/2(beta) = 0.693 . Vd/Cls. Half-life will be a measure of the fluctuation in drug level one may expect with continued administration of a drug while clearance will determine the dose required to achieve a particular steady state level. Liver disease may affect clearance and volume of distribution and so produce changes in half-life; in addition, alterations in plasma binding of drugs may occur and so influence free (unbound) drug levels. It is also possible that the end organ response, particularly in the case of sedative drugs, may be affected by liver disease. Other factors such as age, nutrition, smoking, and concomitant drug therapy may also influence drug elimination in patients with liver disease. At the present time, caution should be exercised in prescribing drugs to patients with liver disease and the dose should be titrated to the clinical response. The development of liver 'function' tests using model or marker drugs may offer some help to the prescriber in the future and enable a less empirical approach.

Plasma acetaminophen elimination was examined in women taking low-dose estrogen oral contraceptive (OC) steroids and in age-matched control women. Fractional rates of elimination and fractional clearances were calculated for each of the metabolic pathways, including oxidation, sulfation, and glucuronidation. The cysteine adduct and mercapturic acid derivative of acetaminophen were used as an index of oxidative biotransformation, a potentially toxic route of metabolism for acetaminophen. Plasma acetaminophen clearance rose from 287 +/- 13 ml/min to 470 +/- 51 ml/min in women taking OC steroids, whereas elimination t1/2 decreased from 2.40 +/- 0.14 hr to 1.67 +/- 0.16 hr. The fractional clearance and rate of elimination of acetaminophen by glucuronidation increased in women taking OC steroids, whereas the clearance and elimination by sulfation did not differ significantly from values in control subjects. Fractional clearance of the cysteine adduct also increased significantly, but clearance of acetaminophen mercapturic acid did not change. These data suggest that the increased clearance of acetaminophen from plasma in women taking OC steroids results from increased glucuronidation of the drug, although the mechanism is not known.Plasma acetaminophen elimination was examined in women taking low-dose oral contraceptives (OCs) and in age-matched control women. Fractional rates of elimination and fractional clearances were calculated for each of the metabolic pathways, including oxidation, sulfation, and glucuronidation. The cysteine adduct and mercapturic acid derivative of acetaminophen were used as an index of oxidative biotransformation, a potentially toxic route of metabolism for acetaminophen. Plasma acetaminophen clearance rose from 287 +or- 13 ml/minute to 470 +or- 51 ml/minute in women taking OCs, whereas elimination t1/2 decreased from 2.40 +or- 0.14 hours to 1.67 +or- 0.16 hours. The fractional clearance and rate of elimination of acetaminophen by glucuronidation increased in women taking OCs, whereas the clearance and elimination by sulfation did not differ significantly from values in control subjects. Fractional clearance of the cysteine adduct also increased significantly, but clearance of acetaminophen mercapturic acid did not change. These data suggest that the increased clearance of acetaminophen from plasma in women taking OCs results from increased glucuronidation of the drug, although the mechanism is not known.

The effects of tetracycline on the synthesis, outward transport, and accumulation of triglyglycerides from [1-14C]oleate were investigated using the isolated perfused rat liver. The effects of the antibiotic on production of CO2, and ketone bodies were studied also. Tetracycline either was added to the medium perfusing livers from normal fed male rats, or alternatively, was administered to rats intravenously (pure tetracycline HCl, or Achromycin, 100 mg/kg body weight) 3 hr prior to removal of the livers for perfusion. The quantity ofoleate infused was sufficient to yield approximately half-maximal rates of output of triglycerides. Under these conditions, on the basis of the isotopic data, the hepatic accumulation of triglycerides derived from the exogenous sources (perfusate 14C free fatty acid) was balanced by a decrease in outward transport triglycerides, whether tetracycline was added directly to the medium perfusing the livers in vitro or was administered to the animals in vivo. Decreases in hepatic oxidation of oleate induced by tetracycline did not appear to be an important mechanism for induction of steatosis. These data suggest that the fatty liver resulting from intoxication by tetracycline results primarily from inhibition of outward transport of triglycerides.

Hepatic encephalopathy may be defined as an alteration in mental state accompanying and due to liver disease. Hepatic dysfunction may be of the chronic type (i.e. cirrhosis) with spontaneous or surgically-induced portal-systemic shunting of blood (portal-systemic encephalopathy, PSE), or caused by acute liver failure (viral or toxic). Encephalopathy, in the former disorder (PSE), is usually insidious in onset, precipitated by some specific insult (i.e. gastrointestinal hemorrhage, azotemia, hypokalemic alkalosis) and is often rapidly reversible with appropriate therapy. In this regard, PSE is unique since treatment is relatively effective despite lack of complete understanding of the pathogenesis of this syndrome. Some 75 percent of such patients respond to rather simple and innocuous therapy within 72 hours and, in fact, lack of improvement is cause to reevaluate the diagnosis.

Our studies in rats clearly demonstrate a significant depression of aminopyrine metabolism in vivo by ether anesthesia. The depression of aminopyrine elimination was shown both by measurements of plasma aminopyrine clearance and by depression of the [14C]aminopyrine breath test. No apparent effect of ether was seen on aminopyrine volume of distribution. The effect of ether was prolonged, as judged by its persistence in the aminopyrine breath test for 3 hr after stopping ether anesthesia. In addition, when ether was administered in combination with a single dose of ethanol, aminopyrine clearance was inhibited significantly more than with ethanol alone. These data not only have a bearing on proper methodologic design of drug clearance studies but also may relate to the effects of some anesthetics on hepatic function.

Fluoxetine is a specific and potent inhibitor of presynaptic serotonin reuptake and has been shown to be a clinically effective antidepressant. Elimination of the drug depends primarily on hepatic metabolism, with formation of a pharmacologically active demethylated product, norfluoxetine. The present study assesses for the first time the effect of chronic liver disease on these processes. Our data show that in stable alcoholic cirrhosis, the elimination of fluoxetine is significantly reduced. The mean t1/2 was 6.6 vs. 2.2 days and plasma clearance was 4.2 vs. 9.6 ml/min/kg for patients with cirrhosis vs. normal volunteers, respectively. In addition, the formation of norfluoxetine was decreased and its clearance was also reduced. Thus, at steady state both fluoxetine and norfluoxetine concentrations will be higher in patients with cirrhosis, unless the dosage is reduced. Conventional liver tests and indocyanine green clearance in cirrhosis did not correlate in a predictive manner with individual patients' elimination of fluoxetine.

The aims of this study were to evaluate the hypothesis that impaired glucuronidation of bilirubin and possibly of drug oxidation in the liver of homozygous (jj) Gunn rats may be due to an altered microsomal milieu. Accordingly, we investigated and compared in vivo and in vitro demethylation of aminopyrine, hepatic cytochrome P-450 levels, microsomal lipid composition, and microsomal membrane fluidity in icteric, homozygous (jj) Gunn rats and in their anicteric heterozygous (jJ) littermates. In both males and females, [14C]aminopyrine demethylation in vivo, using the 14CO2 breath test, was unimpaired in the icteric animals. Likewise, cytochrome P-450 levels in the icteric and nonicteric groups were similar, and aminopyrine kinetics in vitro in the females were comparable in icteric and nonicteric littermates. The main lipid classes were also similar in the homozygous and heterozygous female Gunn rats, whereas only minor changes were seen in the phospholipid fatty acyl composition with a small, but significant, increase in the unsaturated index in the icteric group. Despite this, there was no apparent effect on hepatic microsomal membrane fluidity as measured by the order parameter of I[12,3] and the rotational correlation time of I[1,14] in either female or male sets of homozygous and heterozygous Gunn rats. Our data, therefore, do not support an alteration of composition or fluidity of the microsomal milieu as a mechanism of impaired bilirubin glucuronidation and possibly of oxidation in these animals. They also absolve long-term unconjugated hyperbilirubinemia as a mechanism of hepatic microsomal dysfunction. Our study, therefore, indirectly suggests that abnormal glucuronidation of bilirubin and some other aglycones in homozygous Gunn rats is due to genetic abnormalities involving the enzyme(s) itself.

As part or a systematic study of alcoholism and thiamine absorption, the effect of diet-induced thiamine deficiency and the role of the unstirred water layer on thiamine transport were investigated. Using 3H-labeled dextran as a marker of adherent mucosal volume, jejunal uptake of 14C-labeled thiamine hydrochloride was measured, in vitro, in thiamine-deficient rats and pair-fed controls. Uptake of low thiamine concentrations (0.2 and 0.5 μM) was greater in the thiamine-deficient rats thatn in the controls. In contrast, uptake rates for high thiamine concentrations (20 and 50 μM) were similar in both groups. While ∗J max was unaltered, ∗K m was decreased in thiamine deficiency, suggesting a decrease in unstirred water layer thickness. Accordingly, the thickness of the water layer was measured in both groups of animals and correlated with ∗J max and ∗K m under unstirred and st irred conditions. Without stirring, there was no difference in ∗J max between the two groups. In contrast, both ∗K m and the water layer were reduced in the thiamine-deficient rats. With stirring, ∗J max was not affected, but both ∗K m and the water layer thickness were reduced to similar values in both groups. Reversal of thiamine deficiency resulted in the return of thiamine uptake and the unstirred water layer thickness to control values. These data support the concept of a dual system of thiamine transport and emphasize the role of the unstirred water layer as an important determinant of transport kinetics not only under physiologic situations but also in diet-induced rat thiamine deficiency, a model for a clinical pathological state. The decrease in the unstirred water layer thickness in thiamine deficiency may be also viewed as a possible adaptive mechanism to facilitate absorption of meager supplies of thiamine.

The disposition of chlordiazepoxide (Librium) and diazepam (Valium), compounds which are initially degraded by oxidative processes, differs from that of oxazepam (Serax) and lorazepam (Ativan, drugs which are inactivated by conjugation with glucuronic acid. Liver disease and cimetidine impair the elimination of the former agents, but not the latter two benzodiazepines. In addition, ethanol inhibits the metabolism of chlordiazepoxide and diazepam. The present studies were performed to determine the effect of short-term ethanol administration on glucuronidation and elimination of lorazepam in dogs and humans. Because, in dogs, lorazepam has a high extraction ratio (approximately 0.9) with an anticipated large presystemic elimination, the influence of ethanol on the presystemic (first-pass) elimination of lorazepam was determined. Administration of p.o. lorazepam to five healthy dogs 1 hr after i.v. saline or ethanol (3 gm/kg) reduced the presystemic elimination of lorazepam by 52% (p less than 0.05). In man, lorazepam has a low (approximately by 0.05) extraction ratio and only a small first-pass effect. Short-term administration of ethanol (0.8 gm/kg followed by 0.5 gm/kg p.o. every 5 hr for four doses) reduced i.v. lorazepam clearance by 18% (p less than 0.03). In dogs and man, ethanol did not significantly alter lorazepam t1/2, plasma protein binding, or distribution volume (Vd beta). The results suggest that short-term ethanol administration impairs the conjugation of lorazepam in dogs and man.

The aims of this study were to assess the effect of dietary thiamine deficiency in rats on DNA synthesis and DNA, RNA and protein concentrations of heart, kidney, pancreas and liver. DNA synthesis rates, as determined by [14C]thymidine incorporation, declined in thiamine-deficient (TD) rats with neurologic signs to 36, 52, 32 and 64 per cent of pair-fed control (PFC) values in heart. kidney, pancreas and liver, respectively, 180 min after an intraperitoneal injection of the isotope (P

Both cimetidine therapy and cirrhosis individually interfere with normal elimination of various drugs. Cimetidine is often prescribed in patients with cirrhosis but there is incomplete data on its effect on drug elimination in cirrhotics. The purpose of this study was to address this issue. Eight stable cirrhotics were studied prior to and following 7 days of cimetidine administration, (300 mg orally q.i.d.). Chlordiazepoxide (Librium), which is eliminated by the liver after demethylation, and indocyanine green, which is removed by the liver without biotransformation, were used as probes. Consistent with the concept that cimetidine interferes with drug metabolism by inhibiting microsomal oxidation, chlordiazepoxide clearance in the cirrhotics was inhibited by cimetidine (p less than 0.05), but indocyanine green clearance was unaffected. As shown by us previously (Roberts, R. K. et al., Gastroenterology 1978; 75:479-485), untreated cirrhotics had substantially lower chlordiazepoxide clearance than did controls. The inhibitory effect of cimetidine on chlordiazepoxide clearance was less in cirrhotics than in controls (p less than 0.05). In all subjects, there was excellent correlation between initial clearance and magnitude of depression in clearance after cimetidine, i.e., the larger the initial clearance, the larger the change (r = 0.97, p less than 0.0001). Forty-eight hours after stopping cimetidine, chlordiazepoxide clearance returned to baseline in cirrhotics and controls. Our data demonstrate that cimetidine and cirrhosis may act additively to impair drug metabolism. This effect of cimetidine on chlordiazepoxide clearance is smaller in cirrhotics than in controls, but, because of impaired initial drug elimination in cirrhosis, it may result in adverse clinical effects.

Ammonia intoxication causes loss of consciousness. One postulated mechanism for this stipulates impaired energy metabolism in critical brain sites. The ascending reticular activating system in the brainstem may modulate consciousness. Accordingly, the present study, using micromethods, assessed energy stores in cells from the reticular activating system of mice acutely intoxicated with ammonia. In the early coma period (3.5 min after ammonia) phosphocreatine, adenosine triphosphate and glucose fell significantly while glycogen decreased later. Subsequently during coma, the high energy phosphates returned to normal and supranormal. The maximal fall in these metabolites was not accompanied by a rise in lactate, implying lack of local hypoxia or acidosis. The cells of the posterior colliculus in the same animals failed to show a significant fall in energy stores. These data suggest a selective effect of ammonia on energy metabolism in the cells of the reticular activating system of the brainstem.

Ethanol may enhance the sedative effect of benzodiazepines leading to greater psychomotor impairment, but the mechanism is not clear. The present study was carried out to determine the effect of acute ethanol ingestion on the disposition and elimination of chlordiazepoxide (Librium), a widely used benzodiazepine. Five healthy, 22-39-year-old, male volunteers ingested ethanol 0.8 g/kg as 25% in orange juice 1 h before chlordiazepoxide 0.6 mg/kg was injected intravenously. To maintain plasma ethanol concentrations of 50-150 mg!100 ml for 32 h additional ethanol 0.5 g/kg was given orally every 5 h. Plasma clearance of chlordiazepoxide fell from 26.6 +/- 2.6 ml/min (mean +/- SD) without ethanol to 16.6 +/- 3.1 ml/min (P less than 0.05) after ethanol. There was no change in the volume of distribution and therefore the elimination half-life was prolonged from 7.1 +/- 1.9 h to 11.8 +/- 6.0 h (P less than 0.05) after ethanol. Ethanol also lowered the plasma binding of chlordiazepoxide from 94.7 +/- 0.6% to 93.4 +/- 1.3% (P less than 0.05). The plasma clearance of unbound chlordiazepoxide fell from 468 +/- 51 ml/min to 264 +/- 98 ml/min (P less than 0.05) after ethanol. The plasma level of the metabolite desmethylchlordiazepoxide was higher and its elimination slower after ethanol. Thus using a pharmacokinetic approach this study has demonstrated that short-term ethanol ingestion in moderate doses impairs the elimination of chlordiazepoxide and accounts, at least partly, for the greater sedation that results when ethanol is taken concomitantly.

The effect of nizatidine, a new H2-receptor antagonist, on the hepatic metabolism of three probe drugs was studied in normal volunteers. The drugs studied were chlordiazepoxide and theophylline which are metabolized in part by N-demethylation by the hepatic microsomal cytochrome P-450 system and lorazepam which is conjugated to lorazepam glucuronide. A 7 day course of nizatidine did not interfere with the disposition of any of these therapeutic agents in man.

There is considerable interspecies and interdrug variability in the effect of sex differences and oral contraceptive (OC) steroids on hepatic drug elimination. Their influence on the disposition of chlordiazepoxide has been studied in 11 healthy young men (29 +/- 5 yr), 11 healthy young women (28 +/- 5 yr), and 7 healthy women receiving OC steroids (27 +/- 2 yr) for more than 6 months. The elimination half-life (t1/2(beta)) was longer (from 14.8 +/- 5.9 hr to 8.9 +/- 2.5 hr) and protein binding less (95.5 +/- 1.4% and 97.0 +/- 1.2%) in women than in men. Weight-normalized plasma clearances of total drug did not differ, but the clearance of unbound drug was significantly less in women (8.7 +/- 5.0 ml/min/kg) than in men (15.6 +/- 5.3 ml/min/kg). Women on OC steroids had a lower plasma binding (from 93.6 +/- 1.5% to 95.5 +/- 1.4%) and a higher volume of distribution (from 0.62 +-/ 0.23 l/kg to 0.40 +/- 0.14 l/kg) than women not on OC steroids. The elimination t1/2 was longer (from 24.3 +/- 12 hr to 14.8 +/- 5.9 hr) and the clearance of unbound drug lower (from 5.7 +/- 3.0 ml/min/kg to 8.7 +/- 5.0 ml/min/kg) in women on OC steroids than in those not using them, but these differences were not statistically significant.The effect of oral contraceptives (OCs) on hepatic drug elimination, in this case chlordiazepoxide, was studied in 11 healthy young men, 11 healthy young women, and 7 healthy young women receiving OCs for more than 6 months. Elimination half-life was longer (14.8-8.9 hours) and the protein binding less (95.5 and 97%) in women than in men. When weights were normalized, plasma clearances of total drug did not differ, but clearance of unbound drug was significantly less in women (8.7 ml/min/kg) than in men (15.6 ml/min/kg). Women taking OCs had a lower plasma binding (from 93.6-95.5%) and a higher volume of distribution (from .62-4 1/kg) than women not taking OCs. Elimination half-life was longer (from 23.4-14.8 hours) and clearance of unbound drug lower (from 5.7-8.7 ml/min/kg) in women on OCs than in those not using them, but these differences were not statistically significant.

The liver, by virtue of its extensive array of enzyme activities, plays a vital role in drug metabolism. Moreover, its location in relation to the splanchnic circulation makes it an effective barrier against the systemic distribution of drugs and other noxious agents that might be ingested. In the presence of liver disease, therefore, the transformation of various drugs from pharmaco­ logically active to inactive compounds may be impaired, thus increasing the likelihood of unwanted effects. The presence of liver disease, however, is not the only factor that can influence drug metabolism; numerous other vari­ ables (Table 1), operating either in the external or in the internal environ­ ment, may play a modifying role (1). Among such variables is the coadministration of other drugs, including alcohol, an agent that causes a number of reversible as well as irreversible changes in the biochemical and physiological functions of the body. The present discussion examines major drug interactions and focuses on the effect of liver disease, alcohol, and malnutrition on drug metabolism. To aid in the discussion, the routes of drug metabolism in the liver and key pharmacokinetic principles are re­ viewed first.

The diet plan marketed by the United Sciences of America, Incorporated (USAI) claims to offer "optimal nutrition" for the health of Americans. This claim raises the question, what is an "optimal" diet? Analyses of the four diet products--a fiber energy bar, an omega-3 fatty-acid concentrate, a calorie-control formula, and a master formula of mixed ingredients--raise questions regarding safety and efficacy of this plan. Still further questions focus on endorsement of the USAI diet plan and the relation of endorsement to receiving "grants" from the producer.

Some 30% of patients with cirrhosis die in hepatic coma The clinical pattern is well defined, and the pathophysiology of interactions between liver and brain has been extensively investigated. The challenge now remains to characterize normal brain function. New imaging techniques carry the promise of dramatic breakthroughs.

Cerebral regional concentrations of acetylcholine (ACh) were measured in two acute (with or without portacaval shunt) and one subacute (average 3 days) models of ammonia-induced coma in rats. The animals were sacrificed by total-body or head-focused microwave irradiation which, respectively, decreases or essentially eliminates post mortem degradation of ACh. In the two acute models of coma, normal levels of ACh were found in cortex, midbrain, and brainstem. A small decrease in striatal ACh was noted in rats without portacaval shunt given ammonia, but not in the other acutely intoxicated group. By contrast, in the subacute model (portacaval shunted rat given ammoniated resin by gavage) ACh fell by 14, 20, 33 and 39%, respectively, in the cortex, corpus striatum, midbrain, and brainstem. It is suggested that this decrease in brain ACh is a concomitant finding and not the cause of the coma.

This study is a double "blind" prospective evaluation of the efficacy of antibiotics (Ampicillin) in the treatment of acute alcohol-induced and idiopathic pancreatitis. Fifty-eight patients with acute pancreatitis were randomly divided into antibiotic and non-antibiotic treatment groups. The two groups were comparable clinically at the onset of the study and other than for antibiotics received identical therapy. The patients without antibiotics had a clinical course equal or slightly more favorable than the antibiotic treatment group in all parameters examined. These data indicate that prophylactic use of Ampicillin is not indicated in patients with routine acute alcohol-induced or idiopathic pancreatitis. The role of prophylactic antibiotics in patients with pancreatitis related to biliary calculi and those with more severe varieties of acute hemorrhagic or necrotizing pancreatitis remains to be more clearly defined.

To assess the value of liver-lung scanning in the diagnosis of right subphrenic abscess, 148 scans were reviewed against corresponding charts. Of 91 scans with adequate clinical data, overall scanning error was 19.3% with 14 false positive and 3 false negative scans. Among 49 scans (of the initial group of 91 studies) with presence or absence of actual pathology proved by surgery and/or autopsy, there were 3 true positive, 12 false positive, 29 true negative, and 3 false negative scans. Analysis of data indicated (1) lower accuracy of scan interpretations than generally reported, (2) low specificity for positive scans and high specificity for negative scans, (3) correlations of false interpretations with atypical degrees of liver-lung separation and with scanning defects in liver and lung, and (4) failure of rereading significantly to improve accuracy of interpretation.

The effects of acute and chronic maternal ethanol consumption on in vitro placental uptake of alpha-aminoisobutyric acid (AIB), cycloleucine, L-alanine (Ala), L-leucine (Leu), and L-lysine (Lys) were determined. Ethanol (4 g/kg. po) administered 2 hr prior to sacrifice, reduced (p less than 0.05) placental villous net uptake of cycloleucine and Ala by 29%. Prior chronic ethanol consumption depressed (p less than 0.05) placental uptake of AIB (38%), cycloleucine (45%), Ala (35%), Leu (25%), and Lys (34%). In vitro exposure of previously untreated villous fragments for 2 hr to 2 mg/ml of ethanol reduced (p less than 0.05) the net uptake of AIB and cycloleucine by 24% and 31%, respectively, whereas the minimum concentration of acetaldehyde required to cause a significant inhibition was 310 microM for AIB and 465 microM for cycloleucine. Ethanol (3 mg/ml) had no effect on AIB or cycloleucine net uptake if sodium was omitted from the incubation media. The efflux of AIB (10(-6)M) and cycloleucine (10(-6)M) from villous tissue was unaffected (p less than 0.05) by either ethanol (3 mg/ml) or acetaldehyde (600 microM) and obeyed first order kinetics. It was concluded that acute, and especially chronic, maternal ethanol consumption can depress the placental uptake of a variety of amino acids in the rat and, in the acute setting, the effect was on a sodium-dependent system involved in amino acid influx into placental cells.

Antilirium®, which contains eserine (physostigmine) and benzyl alcohol, is effective in reversing diazepam-induced sleep in man and is capable in vitro of inhibiting the binding of labeled benzodiazepine to both rat and human brain homogenates in a dose-dependent manner. We have examined the constituents of Antilirium and report that both benzyl alcohol and eserine inhibit [3HI-diazepam binding to rat brain in a dose-dependent manner. A major portion of the inhibition of binding found with Antilirium is accounted for by benzyl alcohol. Scatchard analysis of inhibition of benzodiazepine binding by benzyl alcohol reveals loss of binding sites and change in equilibrium dissociation constant. Methanol, ethanol, and butanol did not inhibit benzodiazepine binding. The inhibition by benzyl alcohol may be specific since there was no inhibition of labeled ligand binding to the γ-aminobutyric acid, opiate, muscarinic acetylcholine, or β-adrenergic receptors. The other constituent, eserine, is a competitive inhibitor. While eserine is a more potent inhibitor at the benzodiazepine receptor than is benzyl alcohol, it is also much less specific. Eserine inhibited binding of labeled ligand to the γ-aminobutyric acid, opiate, and muscarinic acetylcholine receptors. The inhibition of benzodiazepine binding to brain in vitro by Antilirium and its constituents, eserine and benzyl alcohol, may be the explanation, at least in part, for the reversal by Antilirium of diazepam-induced narcosis in viva, without postulating a cholinergic mechanism for the in vivo effect.

The effects of ethanol alone or in combination with caffeine on fetal viability, growth and placental amino acid uptake function in the rat were examined. Compared to pair-fed control values, chronic ethanol exposure reduced fetal survival by 24%, fetal weight by 17%, along with weight decreases of fetal brain (16%), heart (31%), and kidney (48%) as compared to pair-fed control values. Placental weight was significantly increased by 17%. Concomitant caffeine intake generally exacerbated these effects with a further reduction in fetal survival, fetal body and visceral weights. Caffeine intake alone had no consistent effect on these parameters. Acute in vitro (3 mg/ml) and chronic in vivo ethanol exposure reduced placental net uptake of alpha-aminoisobutyric acid (AIB) by 32 and 45%, respectively. Neither acute in vitro (10 micrograms/ml) nor prior chronic caffeine exposure altered villous AIB uptake. Concomitant ethanol and caffeine treatment increased AIB uptake as compared to ethanol alone. However, AIB uptake continued to be reduced (by 22%) as compared to pair-fed control values.

Using a single cotyledon perfusion model, the placental transport of four H2-receptor antagonists, cimetidine, famotidine, nizatidine, and ranitidine, was determined and compared using normal term human and normal preterm baboon placentas. In both the human and baboon placentas, the transport of each agent was similar whether administered singly or in combination with the other drugs. Drug transport was the same in both directions, maternal-to-fetal and vice versa, indicating a lack of preferential transfer. The H2-receptor antagonists were transported at about 40% the rate of the freely diffusable reference compound, antipyrine. There were no significant differences between the human and baboon in any of the parameters of placental function evaluated. Placental glucose and oxygen consumptions, and lactate production were comparable in the human and baboon preparations. The transport and clearance of each of the H2-antagonists were similar in each species.

This study addresses the mechanism of transport of the H2-receptor antagonist, cimetidine, by the human placenta. A 4-h recycling perfusion of a single placental cotyledon of normal, term, human placenta was used. At a maternal concentration of 1 microgram/ml, cimetidine clearance from the maternal circulation was 0.58 +/- 0.16 ml/min per g placenta, a rate about one third that of antipyrine. There was no evidence of cimetidine metabolism by the placenta. Transfer of cimetidine from maternal to fetal compartments showed no saturation kinetics and was not inhibited by putative carrier competitors. Cimetidine did not accumulate against a drug concentration gradient. Fetal clearance of cimetidine was similar to maternal clearance. Studies with placental apical vesicles confirmed lack of saturability of cimetidine transport and of its concentration within vesicles. Thus, (a) cimetidine is transported across the human placenta bidirectionally at a rate about one third that of antipyrine, (b) the drug is not metabolized by the placenta, and (c) the transport is a passive one.

Previous studies have indicated that acute, and especially chronic, maternal ethanol consumption can depress placental uptake of various amino acids. Since the fetal cell itself represents a second barrier to nutrients, one which may be altered by ethanol exposure, the effects of ethanol on amino acid net uptake by rat fetal hepatocytes was addressed. The present study determined that ethanol stimulated amino acid net uptake by fetal hepatocytes grown in monolayer culture. Fetal liver cells were grown in custom Williams' E medium (without L-arginine and with L-ornithine) and exposed to epidermal growth factor (0, 1, 2 or 5 ng per ml) and ethanol (1.7 ± 0.1 or 3.9 ± 0.2 mg per ml). Addition of ethanol (3.9 mg per ml) to the culture medium completely blocked measurable cell replication during a 48-hr exposure period. Fetal hepatocytes exposed to ethanol accrued both protein and water in a parallel fashion, both in excess of that by control cells. Ethanol (1.7 and 3.9 mg per ml) for 48 hr stimulated α-aminoisobutyric acid net uptake by fetal hepatocytes (p < 0.05). Efflux was not affected (p < 0.05). The onset of this significant stimulation of net uptake was progressive and required in excess of 6 hr of contact with ethanol. This ethanol stimulation of α-aminoisobutyric acid net uptake persisted for at least 24 hr following ethanol withdrawal. The component(s) of α-aminoisobutyric acid net uptake stimulated by ethanol was independent of extracellular Na+. In addition, ethanol stimulated net uptake of two other marker amino acids, methyl-α-aminoisobutyric acid and cycloleucine (54 and 128%, respectively, p < 0.05). In summary, these data suggest: (i) ethanol can stimulate the net uptake of amino acids by fetal hepatocytes while not affecting efflux; (ii) this effect requires an exposure period in excess of 6 hr and is not rapidly reversible, and (iv) ethanol exposure (3.9 mg per ml) totally prevents fetal hepatocyte replication and causes a 3- to 4-fold increase (accumulation) in cellular protein and water.

Our aim was to investigate the possible interaction of acute ethanol (E) with the metabolism of other drugs by microsomes isolated from immature and mature rat livers and placenta. The effects of acute in vitro E exposure on the N-demethylation of [14C]aminopyrine and [1-14C]methylcaffeine by these tissues were determined. In addition, the effects of ethanol on these two enzyme systems from male and female livers were compared along with an analysis of ethanol and cimetidine inhibitory interactions. The degree (percentage) of inhibition by acute E (1-3 mg/ml) varied with both age and sex. Aminopyrine demethylase activity was inhibited by E to a greater degree (p less than 0.05) in the adult female than the male. However, when inhibition was expressed in absolute terms (control minus inhibited activity), these inhibitory values varied in direct proportion to initial (control) enzyme activity. Thus, E reduced aminopyrine demethylase from adult male microsomes by 4 times that in the female and in excess of 1000 times the absolute inhibition observed in fetal liver regardless of E concentration. A similar pattern of sex and age differences in caffeine demethylase response to E was observed except that absolute differences in inhibition were less due to smaller variation in control values. In addition, placental caffeine demethylase was highly sensitive to E inhibition (51% at 3 mg/nl) but not to the extent of caffeine demethylase from fetal liver (75% at 3 mg/nl). Finally, it was demonstrated that E interacts with cimetidine in a manner that may be additive.

The clinical course of 19 patients with pancreatic phlegmon, as diagnosed by computed tomography (CT) and clinical criteria, was assessed retrospectively and compared to that of eight patients with pancreatic abscess diagnosed either at surgery or with percutaneous aspiration. Controls consisted of 55 patients with uncomplicated acute pancreatitis without CT scans and 11 patients with acute pancreatitis in whom CT scans were negative or only consistent with acute pancreatitis (no phlegmon). The age, sex, and presumed etiology of the pancreatitis were not significantly different in the four groups. Patients with phlegmon had a higher incidence of severe pancreatitis as defined by Ranson's criteria, presence of an abdominal mass, as well as a longer duration of fever, abdominal pain and leukocytosis than controls without CT scans. With the exception of a palpable abdominal mass and fever lasting over five days, the results were similar when comparing the phlegmon group and controls with CT scans, although the severity of the disease and prolonged abdominal pain tended to be increased in the former patients. There was no statistically significant difference in clinical or laboratory criteria between the phlegmon and abscess groups, although the latter group had longer hospital stays and periods with no oral intake (npo). Management of patients with phlegmon tended to include TPN, longer npo periods, antibiotics, and longer hospital stay than in controls without CT scans. Controls with CT scans were managed similarly to the phlegmon group because of prolonged amylase elevation and abdominal pain. Percutaneous aspiration was successful in differentiating abscess from phlegmon in five of six cases. Major complications were rare in the phlegmon group and spontaneous resolution was the rule. Pancreatic phlegmon is a distinct clinical/radiologic entity which may be very difficult to differentiate clinically from pancreatic abscess. Early percutaneous thin-needle aspiration of the inflammatory mass (under CT guidance) seems to be the diagnostic procedure of choice. Management is nonsurgical unless complications arise. The role of TPN and antibiotics is unknown, and controlled studies of these therapeutic approaches in pancreatic phlegmon are needed.