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(13)C-Aminopyrine breath test ((13)C-ABT) is a non-invasive, dynamic, quantitative liver function test, and the model for end-stage liver disease (MELD) is a recognised biochemical score used to predict survival in patients with cirrhosis.The purpose of this study was to evaluate the relationship between the (13)C-ABT and MELD score in a cohort of cirrhotic patients and, moreover, to assess the prognostic value of (13)C-ABT results in the same group of patients.Forty-six patients with cirrhosis and without hepatocellular carcinoma who underwent (13)C-ABT and who had at least 1-year follow-up were prospectively included in this study. MELD score was calculated at entry into the study in all patients. End-points of the study were 1-year liver-related death or liver transplantation.(13)C-ABT %dose/h at 30 min (%dose/h30) results showed significant, inverse correlation with MELD scores (r = -0.414, P = 0.004). During 1-year follow-up nine patients died (19.6 %) and two were transplanted (4.3 %). Median (13)C-ABT %dose/h30 results (3.2 vs. 1.8) were significantly higher in patients who survived as compared to those who died or underwent transplantation (P = 0.04). Receiver operating characteristics curves showed that a (13)C-ABT %dose/h30 cut-off of 2.0 had the best accuracy (c-index = 0.717) in assessing 1-year prognosis.We observed a correlation between a flow-independent quantitative liver function test and the MELD score, and found that the (13)C-ABT may accurately provide long-term prognostic information in cirrhotic patients.

Helicobacter pylori eradication therapy is commonly prescribed in the general population. Treatment consists of drugs that are mainly metabolized by the liver cytochrome P-450 (CYP) enzymatic pool. Most H. pylori-infected patients often take drugs for comorbid illnesses, therefore increasing the potential for drug-drug interactions. We aimed to evaluate the interactions of rabeprazole, clarithromycin, and metronidazole 1-week H. pylori eradication therapy with CYP-dependent liver metabolic function in clinical practice. Ten patients referred to our unit for H. pylori infection underwent 1-week eradication therapy with rabeprazole (20 mg, b.i.d.), clarithromycin (500 mg, b.i.d.), and metronidazole (500 mg, b.i.d.). We chose the 13C-aminopyrine breath test (13C-ABT) to evaluate CYP-dependent liver function since it is noninvasive and nonharmful. All patients underwent 13C-ABT at three time points: before therapy (to), at the end of therapy (t8), and after 1 month of follow-up (t38). Mean 13C-ABT dose/hr (t0 = 14.0 +/- 5.4, t8 = 13.5 +/- 4.0, t38 = 16.1 +/- 5.6) as well as 13C-ABT cumulative dose (t0 = 2.4 +/- 1.1, t8 = 2.4 +/- 0.8, t38 = 2.6 +/- 1.0) were not statistically different at the three time points of the study. These results did not seem to be influenced by drugs being administered concomitantly. In everyday clinical practice rabeprazole-based H. pylori eradication therapy does not seem to display any significant interactions with CYP-dependent liver function, even in patients on multiple drugs.

We tested sonicates of Helicobacter pylori, H. mustelae, and H. felis for inhibition of acid secretion in rabbit and ferret isolated gastric glands. Three H. pylori strains, two of three H. mustelae strains, and two H. felis strains significantly inhibited acid secretion in rabbit cells by 95.2-93.3%, 55.9% and 96.4%, and 83.4-96%, respectively. All Helicobacter strains examined inhibited acid secretion by ferret cells by 65.3-76.8%, 89.1-97.6%, and 85.8-92.8%. H. pylori inhibited acid secretion after stimulation with histamine and isobutylmethylxanthine or with 8-bromo-cyclic adenosine monophosphate (P0.05 for all tests). These findings demonstrate that acid inhibition is a property common to the three Helicobacter species tested. It occurs independently of the mammalian origin of the parietal cell, and it does not involve blockade of histamine-2 receptors.

The purpose of this study is to evaluate the diagnostic value of the following tests in the assessment of patients with chronic liver disease (CLD) and cholestatic syndrome (CS): (1) aminopyrine breath test, measuring 14CO2 excretion in the expired air, (2) peripheral clearance of [99mTc]EHIDA, and (3) postprandial levels of glycocholic acid (GCA) and glycochenodeoxycholic acid (GCDCA). The results indicate that: (1) 14CO2 2-hr excretion rate is a specific and sensitive marker of liver function, with good correlation with postprandial bile acid levels, [99mTc]EHIDA retention, and the conventional tests of serum albumin and prothrombin time. (2) Peripheral clearance and retention of [99mTc]EHIDA increased in both groups of CLD and CS vs controls, but it does not discriminate between the two. (3) Postprandial bile acids were elevated in CLD, particularly those of GCDCA, whereas GCA levels were significantly elevated in CS compared with CLD. This may be due to increased synthesis and entry into the blood. (4) The combination of [14C]aminopyrine breath test and postprandial levels of GCDCA enhance the diagnostic value, specificity, and sensitivity in the assessment of patients with CLD.

Interactions with the hepatic cytochrome P-450 microsomal enzyme system, as evidenced by statistically significant changes in pharmacokinetic parameters, have been described with some H2-receptor antagonists. Omeprazole is the first of a new class of antisecretory agents inhibiting gastric secretion by blocking hydrogen potassium ATPase. Omeprazole contains a benzimidazole moiety and thus has the potential to interact with the cytochrome P-450 enzyme group. In vitro, in vivo and human clinical studies have assessed whether such an interaction occurs, and the potential clinical consequences, in patients receiving omeprazole therapy. In vitro studies have demonstrated that omeprazole influences O-deethylation and N-demethylation in liver microsomes and the clearance and elimination half-life of antipyrine in isolated perfused liver preparations. Overall, the studies reviewed suggest that omeprazole has a differential affinity toward specific cytochrome P-450 isozymes. In vivo animal studies have demonstrated that omeprazole prolongs pentobarbital sleep times and half-life and decreases [14C]-aminopyrine elimination. Human clinical studies have not demonstrated the "all or none" effect of omeprazole on cytochrome P-450-mediated drug interactions, as is seen with cimetidine. These studies confirm in vitro findings that omeprazole is a differential inhibitor of drug metabolism: interactions have been demonstrated with the model drugs aminopyrine and antipyrine, and the therapeutic drugs diazepam, phenytoin, and warfarin but not with theophylline or propranolol. Although caution should be exercised when initiating omeprazole therapy in patients taking concomitant diazepam, warfarin, and phenytoin, clinically significant drug interactions appear unlikely.

The accumulation of [14C]aminopyrine (AP) is a valuable and widely used method to probe acid secretion of gastric glands and parietal cells. Usually, the dry weight of glands is used to normalize the AP accumulation ratio, and since the nonhomogeneity of the suspension makes it impossible to evenly distribute glands by simple pipetting, it is necessary to scrupulously dry and weigh each and every experimental sample. Thus, massive, time-consuming procedures of tube drying and weighing are involved. Moreover, the weighing of approximately 1 mg dried gland samples in a 1-g Eppendorf tube introduces considerable sample variance. Here, we present a modified protocol to simplify the AP accumulation method by introducing a generic 3H labeling of protein for normalization. Freshly isolated glands were treated with high specific activity 3H-labeled succinimidyl propionate (3H-succ, 60 Ci/mmol) for 10 min at room temperature during the normal isolation/washing procedure. This reagent reacts with primary amines, and even at normal cell pH the efficiency of reaction (25-30%) is more than adequate. The 3H-labeled glands are then processed normally with simultaneous monitoring of 3H (representing gland amount) and AP (representing the extent of acid accumulation) in separate energy windows of a liquid scintillation counter. Dose- and time-dependent efficiency of 3H labeling were evaluated. The relations between labeling and gland protein and dry weight were linear. No detrimental effects of reagent were noted in the useful range of 1-3 nM 3H-succ. Although some limited sample weighing or protein determination must be made for each batch of 3H-labeled glands, this method avoids massive tube weighings and provides the convenience of double label counting with a highly reproducible method for normalizing data.

The aminopryine breath test (ABT) measures hepatic reserve in patients with acute and chronic liver disease and gives an assesment of the hepatic function in patients undergoing major liver surgery. Aminopyrine is metabolized by the mixed cytochrome P-450 system, which can be influenced by many foreign compounds and drugs. Whether these foreign compounds and drugs can influence the results of the ABT has seldomly been tested. We studied three groups: Healthy female volunteers, either normally menstruating or taking oral contraceptives, were asked to perform a [13C]ABT during the time of the menses and at midcylce. Healthy volunteers were asked to perform a ABT after consuming 30 g of alcohol. Healthy volunteers were asked to perform a ABT after consuming 250 ml of grapefruit juice. The 13C/12C ratio in expired air was measured by gas isotope ratio mass spectrometry.

Our aim was to compare color-coded Doppler sonography (CCDS) and quantitative testing of liver function (QTLF) in patients with chronic hepatitis C. In all, 74 patients with chronic hepatitis C and mild fibrosis underwent QTLF, which included aminopyrine breath test (ABT), galactose elimination capacity (GEC), sorbitol clearance (SC), and indocyanine green clearance (ICG). Hepatic artery velocity and resistance index (HA-V, HA-RI) as well as portal vein velocity (PV-V) were measured by CCDS. ABT, GEC, and PV-V were significantly reduced, whereas SC1, ICG, HA-V, and HA-RI showed normal levels. There was a significant correlation between reduction in PV-V only with GEC and ABT. QTLF did not correlate with HA-V and HA-RI. In conclusion, in hepatitis C patients with liver fibrosis, ABT and GEC are decreased significantly, which was paralleled by a reduction of PV-V. Unexpectedly SC1 and ICG, the classical hepatic perfusion parameters, do not correlate with the parameters measured by CCDS.

The effects of inflammatory cytokines induced by Helicobacter pylori infection on acid secretion have not been well defined. The purpose of this study was to investigate the direct effects of these cytokines on parietal cells isolated from guinea pigs. We examined the effects of human recombinant IL-1beta (0.05-100 ng/ml), IL-8 (2-256 ng/ml), and TNF-alpha (0.625-80 ng/ml) on acid secretion stimulated by three secretagogues (10(-4) M histamine, 10(-4) M carbachol, and 10(-5) M tetragastrin) and on basal acid secretion from isolated parietal cells, which was measured by the aminopyrine accumulation method. None of three cytokines showed any significant effects on stimulated or basal acid secretion from isolated guinea pig parietal cells. We concluded that inflammatory cytokines induced by Helicobacter pylori infection may affect acid secretion through mechanisms other than direct actions on parietal cells.

The [13C]aminopyrine breath test measures hepatic mixed function oxidase activity. The cumulative percent dose recovered over 2 hr is a sensitive indicator of hepatic dysfunction; valuesor = 7.0% have been shown to indicate severe liver disease. Previous studies have suggested that the test results may be influenced by the use of oral contraceptives steroids. We compared the results from five non-oral contraceptive-using women with those from 31 women whose duration of oral contraceptive steroid usage ranged from 4 to 204 months. The women were taking one of four oral contraceptive formulations that differed in the amounts of estrogen (20, 35, or 50 micrograms with 1 mg progesterone) and progesterone (35 micrograms estrogen with stepped levels of progesterone of 0.5, 0.75, and 1.0 mg). The [13C]aminopyrine breath test was performed on days 21 and 28 of the menstrual cycle. Cumulative percent dose recovery values among the normal menstrual cycle of non-oral contraceptive steroid-using women were 12.1 +/- 1.6 and 11.8 +/- 1.5% (mean +/- SD). In contrast, oral contraceptive steroid users showed a marked reduction in cumulative percent dose recovery at 21 days, averaging 6.1 +/- 2.3% (P0.001), and returned to normal values (10.2 +/- 3.5%) at 28 days in most women(seven days after oral contraceptive steroid usage was paused). The adverse impact on hepatic mixed function oxidase by oral contraceptive formulations did not differ on the basis of estrogen or progesterone content. The adverse impact of oral contraceptive usage on the mixed function oxidase activity measured by the [13C]aminopyrine breath test must be considered for women of childbearing potential.

Seventy-eight patients with cirrhosis were prospectively followed for up to 20 months, on the average. At entry into the study, galactose elimination capacity, aminopyrine breath test, and ICG clearance were measured. At the end of the study, 27 patients had died. Univariate analysis using the Kaplan-Meier method showed that both quantitative liver function tests (galactose elimination capacity: P less than 0.025; aminopyrine breath test: P less than 0.001; ICG clearance: P less than 0.005) and common clinical and biochemical data (encephalopathy: P less than 0.001; ascites: P less than 0.001; serum bilirubin: P less than 0.005; serum albumin: P less than 0.001; prothrombin index: P less than 0.05) were significant predictors of survival. To investigate whether quantitative liver function tests could contribute to a better definition of the prognosis, once Pugh score had already been taken into account, a multiple regression analysis according to the Cox model was performed. Pugh score and galactose elimination capacity resulted in the only independent prognostic covariates. From them a prognostic index was calculated, and the model was validated in an additional sample of 70 patients investigated according to the same protocol. The contribution GEC gave to the assessment of overall prognosis over that obtained using the Pugh score was slight, as estimated by the statistical parameters of the Cox's model, but was significant as assessed by a ROC curve analysis (P = 0.05). These data show that all quantitative liver function tests were predictors of survival in cirrhosis, and that the galactose elimination capacity added some new prognostic information to those already available using the Child-Turcotte-Pugh classification.

Physical exercise and physical training are known to affect several aspects of hepatic metabolism. To assess whether adaptation to long-lasting exercise modifies microsomal drug metabolism, 8 long-distance runners were compared with a group of medical students having significantly lower maximal rates of oxygen consumption. At rest the hepatic galactose elimination capacity and the indocyanine green plasma disappearance rate used as reference methods were the same in both groups. The plasma clearance of ([14C]dimethylamine) aminopyrine and the kinetics of 14CO2 in breath did not differ either. It is concluded that adaptation to long-lasting exercise can occur without evidence for changes in hepatic galactokinase activity, liver blood flow, or microsomal metabolism of aminopyrine.

The effects of U-46619, a stable analogue of the prostaglandin endoperoxide PGH2, were studied on canine gastric acid secretion, gastric mucosal blood flow, and secretion of mucus into gastric juice and compared to those of PGE2. U-46619 was approximately four and three times as potent as PGE2 in inhibiting acid secretion and stimulating mucus secretion, respectively. When infused at a low dose, U-46619 inhibited acid secretion directly without causing a decrease in the ratio of mucosal blood flow to volume rate of secretion (R), this effect being similar to that observed for PGE2. However, unlike PGE2, U-46619 when administered in a higher dose caused a decline in R while decreasing acid secretion and mucosal blood flow, suggesting a primary restriction of blood flow. The antisecretory effects of arachidonic acid may be due in part to the endogenous formation of prostaglandin endoperoxides as opposed solely to prostaglandin formation. Considering the antisecretory and mucogenic actions of U-46619, nontoxic analogues of prostaglandin endoperoxides may be of value as antiulcer agents.

Adenosine receptors that modulate adenylate cyclase activity have been identified recently in a number of tissues. Adenosine A2 receptor is stimulatory to adenylate cyclase, whereas adenosine A1 receptor is inhibitory to adenylate cyclase. We investigated the effect of adenosine and its analogs on [14C]aminopyrine accumulation by rabbit parietal cells. Rabbit gastric mucosal cells were isolated by enzyme digestion. Parietal cells were enriched by nonlinear percoll gradients. [14C]Aminopyrine accumulation was used as an indicator of acid secretion. The effect of 2-chloroadenosine on histamine-stimulated [14C]aminopyrine accumulation was studied. The effects of N-ethylcarboxamideadenosine, 2-chloroadenosine, stable analogs of adenosine, and adenosine on [14C]aminopyrine accumulation were assessed. Cyclic AMP content of parietal cells was determined by radioimmunoassay. Histamine and carbachol, known secretagogues, stimulated [14C]aminopyrine accumulation. 2-Chloroadenosine did not suppress histamine-stimulated [14C]aminopyrine accumulation. 2-Chloroadenosine, N-ethylcarboxamideadenosine, and adenosine dose dependently increased [14C]aminopyrine accumulation. The order of potency was N-ethylcarboxamideadenosine greater than 2-chloroadenosine greater than adenosine. 8-Phenyltheophylline and theophylline, adenosine-receptor antagonists, or cimetidine did not have significant effects on the increase of AP uptake induced by 2-chloroadenosine. Coadministration of dipyridamole, and adenosine uptake inhibitor, augmented the effect of adenosine on [14C]aminopyrine accumulation. 2-Chloroadenosine, N-ethylcarboxamideadenosine, and adenosine each induced a significant increase in cellular cyclic AMP. We conclude that there may be adenosine A2 receptors on rabbit parietal cells which modulate gastric acid secretion.

Twenty-eight patients with histologically confirmed cirrhosis were followed for up to 3.8 years after [14C]aminopyrine breath analysis. Survival rates were calculated by life-table method and outcome analyzed by log rank test. A normal breath test score was associated with a higher probability of survival than a low score, although the difference was not statistically significant. A normal serum albumin was a better predictor of outcome. Survival curves constructed according to the results of breath analysis and serum albumin differed in that the former appeared to predict early survival and the latter late survival. For this reason, data were reanalyzed by subjects' results for both tests. A normal breath test score and a normal serum albumin was associated with a significantly higher probability of survival than an abnormal result for either test.

Thirty patients with cirrhosis were evaluated with the 2-hr [14C]aminopyrine breath test (score) and with conventional liver tests. Of the 30 patients, 24 also had current liver biopsies. There was a good correlation between necroinflammatory activity in the 24 cirrhotic liver biopsies and the 2-hr aminopyrine scores. All five patients who had at least grade 2 necroinflammatory activity on their biopsy had an abnormal prothrombin time (greater than 3.5 sec above control) and their aminopyrine score was less than 2%. The correlation was good between the 2-hr aminopyrine score and the prothrombin time (seconds over control). No correlation was found between the 2-hr aminopyrine score and either the serum aspartate aminotransferase (SGOT) or any other liver test except for the prothrombin time. It seems that the 2-hr aminopyrine score and prothrombin time are more likely to give a quantitative estimate of total functioning parenchymal mass which is left unaffected by hepatocellular disease in cirrhosis, than the other commonly used liver tests.

The determination of of 14CO2 in breath after oral administration of [14C]aminopyrine has been proposed as a quantitative liver function test. In order to shorten the procedure and avoid misinterpretations related to variable rates of intestinal absorption, the [14C]aminopyrine breath test (ABT) was performed after intravenous administration of [14C]aminopyrine in 21 controls and 89 patients with biopsy-proven liver disease. The specific activity of the first hour sample corrected for body weight (SA1) was the most discriminant expression of breath data. The SA1 value, expressed as the percentage of the administered dose, was 0.86 +/- 0.1% (mean +/- SD) in controls and significantly less in patients (0.46 +/- 0.31%). Low values were observed in patients with untreated chronic active hepatitis (0.16 +/- 0.13%), alcoholic cirrhosis (0.2 +/ 0.15%0, and untreated postnecrotic cirrhosis (0.47 +/- 0.17%). In contrast, normal values were obtained in chronic persistent hepatitis (0.86 +/- 0.13%) and 58% of noncirrhotic alcoholic liver diseases (0.83 +/- 0.27%). The results of duplicate studies were reproducible and SA1 correlated with other conventional liver function tests, including 45-min BSP retention. Among these, ABT was the most sensitive screening test for the presence of cirrhosis, especially in alcoholic patients, where it allowed a sharp distinction between cirrhotic and noncirrhotic cases. The results obtained in chronic hepatitis suggested that ABT may provide a reliable index of the activity of the disease. In our hands, intravenous ABT, performed over a 1-hr period, was a fast, sensitive, and discriminant liver function test.

The [14C]aminopyrine breath test (APBT) score, an estimate of hepatic mixed-oxidase function, was evaluated in 21 consecutive patients wih active nonalcoholic chronic liver diseases. Ten had primary biliary cirrhosis (PBC) and 11 had chronic active hepatitis (CAH). The APBT score was normal or elevated in patients with PBC (P less than 0.001), and lower than normal in CAH patients (P less than 0.01); 10.5 +/- 1.6 and 3.5 +/- 1.86, respectively, vs control 7.65 +/- 1.15 (mean +/- SD). The 11 patients with CAH included two middle-aged women who displayed ambiguous severe intrahepatic cholestasis. There was no overlap between the APBT scores of the 10 PBC and 11 CAH patients. These initial data suggest that the APBT may be helpful in the differentiation of PBC and CAH, including misleading cholestatic forms of CAH.

To determine whether the aminopyrine breath test reflects the presence of increased pericentral fibrosis, steatonecrosis, and cirrhosis following jejunoileal bypass, 21 patients were evaluated with liver biopsies, liver chemistry tests, 45-min bromosulfothalein retention tests, and aminopyrine breath tests prior to bypass and at 3, 6, and 12 months thereafter. Following bypass, 15 biopsies demonstrated increased pericentral fibrosis, steatonecrosis, or cirrhosis, and 35 biopsies revealed increased fatty infiltration alone. Although the aminopyrine breath test results were significantly lower in patients with increased pericentral fibrosis, steatonecrosis, and cirrhosis at 6 and 12 months following bypass (P less than 0.05), this test had a positive predictability of only 0.67. An abnormal AST had a positive predictability of 0.87. Other liver function tests were less reliable in identifying patients with potentially progressive lesions following bypass. Thus, the AST is more useful than the aminopyrine breath test in reflecting increased pericentral fibrosis, steatonecrosis, and cirrhosis following jejunoileal bypass. The nonspecific effects of obesity and increased fatty infiltration of the liver following jejunoileal bypass may account for the low predictability of the aminopyrine breath test.

The possibility that cyclic AMP in gastric juice is derived from plasma by simple clearance was evaluated. The effect of exogenous cyclic AMP administration (1 mg/min) on radioimmunoassayable cyclic AMP in plasma and gastric juice was studied in dog stomach during histamine (8--16 micrograms/kg/hr) infusion. Experiments were performed in vagally denervated fundic (Heidenhain) and in innervated gastric pouches. During infusion of cyclic AMP with histamine, plasma cyclic AMP concentration rapidly increased 500-fold. Simultaneously, gastric juice cyclic AMP levels decreased almost 50%. In contrast, dibutyryl cyclic AMP infusion increased gastric juice cAMP concentration 5-fold, suggesting that the gastric mucosa is more permeable to dibutyryl cyclic AMP. In Heidenhain pouch experiments the clearance of dibutyryl cyclic AMP into gastric juice was only 1.5% of the clearance of aminopyrine. It appears that plasma clearance of cyclic AMP fails to account for most of the cyclic AMP present in gastric juice.

Effects of pentagastrin, histamine, PGI2, and vasopressin on gastric mucosal blood flow (GMBF) in innervated stomaches of anesthetized dogs were measured by means of the hydrogen clearance method, using a contact electrode. The results were compared with findings obtained with the aminopyrine (AP) clearance method in Heidenhain pouch preparations. Pentagastrin at 2 and 8 micrograms/kg/hr had no effects on GMBF, as measured by the hydrogen clearance method, but there was a marked increase in GMBF when the AP clearance method was used. Histamine at 40 or 160 micrograms/kg/hr tended to reduce or significantly reduced GMBF when measured with the hydrogen clearance method, but there was a significant increase in GMBF with the AP clearance method. Both PGI2 (3 or 30 micrograms/kg/hr) and vasopressin (0.06 or 0.25 units/kg/hr) reduced GMBF as determined by both methods. These results indicate that the hydrogen clearance method is advantageous for detecting regional GMBF but is disadvantageous when attempting to detect the effects of agents which increase GMBF.

The effect of experimental hepatobiliary injury on drug metabolism was studied in a series ofin vivo andin vitro experiments in rats.In vivo aminopyrine elimination was measured by14CO2 breath analysis. This measure was compared with anin vitro estimate of the drug-metabolizing enzyme capacity of the whole liver (aminopyrine-free intrinsic clearance, Vmax/Km). The degree of hepatobiliary injury was measured by means of BSP biliary excretion. Two surgical models were studied: severe (complete bile duct obstruction) and mild (selective bile duct obstruction); as well as two drug-induced models: severe (alpha-naphthylisothiocyanate, ANIT) and mild (ethinyl estradiol). In the surgical models, only the complete-bile-duct-obstructed rat had a significantly decreased breath elimination rate of14CO2, 58% of control (P

Chronic infection with hepatitis B virus (HBV) results in a spectrum of hepatic abnormalities ranging from minimal liver dysfunction to severe liver failure. These patients provide an opportunity to examine the relationship between the evolution of the liver disease and the ability to metabolize drugs. We have examined hepatic drug disposition in patients with chronic persistent hepatitis, chronic active hepatitis, and cirrhosis due to HBV infection. Four model drugs were used: two low-extraction capacity-limited drugs (antipyrine and aminopyrine) and two high-extraction flow-limited drugs (ICG and lidocaine). The disposition of the four drugs tested was comparable to that of healthy controls in patients with chronic persistent hepatitis, chronic active hepatitis, and mild cirrhosis. In patients with severe cirrhosis (as defined by the presence of ascites, encephalopathy, or large esophageal varices), there was a significant impairment in the aminopyrine breath test (−31%) and in the clearance of antipyrine (−53%), lidocaine (−49%), and ICG (−54%). These results indicate that impairment of drug clearance occurs only late in the evolution of HBV-related chronic liver disease. This is in keeping with the known slow and insidious progression of the disease.

Isolated canine parietal cells were used to study the ability of misoprostol to inhibit acid secretion in the presence of a number of acid secretagogues. Misoprostol inhibited histamine-stimulated acid secretion in a dose-dependent and noncompetitive manner. A concentration of 2-3 X 10(-9) M misoprostol inhibited maximal histamine-stimulated acid secretion by one half. Misoprostol had little to no effect on acid secretion stimulated by carbachol and dibutyryl cAMP, had no effect on the acid secretion directly stimulated by pentagastrin, and only modestly inhibited acid secretion stimulated by forskolin. Misoprostol noncompetitively inhibited cAMP formation in response to histamine, with an IC50 value similar to that for the inhibition of histamine-stimulated acid secretion. These results indicate that: (1) misoprostol specifically inhibits histamine-stimulated acid secretion in parietal cells, and (2) the antisecretory action of misoprostol is closely related to the reduction of histamine-stimulated cAMP formation with the site of major action most likely in the coupling process between histamine H2 receptor sites and histamine-sensitive adenylate cyclase.