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Acid secretion was measured after a six-week standard treatment with cimetidine in ten patients each with healed or non-healed duodenal ulcer, and the drug's pharmacokinetics studied. There was no difference between the two groups with respect to fasting concentration of cimetidine (compliance), the area under the plasma-level curve, as well as renal excretion (bioavailability) and the period of effective plasma concentration. Maximal secretion during cimetidine treatment was also identical in the two groups. On the other hand, basal secretion in the group of treatment failure was significantly increased (P less than 0.05). Basal secretion during administration of cimetidine can be used as a prognostic criterion for the healing of duodenal ulcer.

There are conflicting data on the existence of significant first-pass metabolism of alcohol (ethanol) in the human stomach and its inhibition by histamine H2-receptor antagonists. Alcohol is predominantly metabolised in the liver by the microsomal alcohol oxidising system, alcohol dehydrogenase (ADH) and a catalase enzyme. Histochemical and kinetic studies have revealed several ADH isoenzymes in the gastric mucosa with different kinetic properties. After small oral doses of alcohol first-pass metabolism in the stomach occurs, as shown by reduced area under the plasma concentration-time curve (AUC) compared with intravenous or intraduodenal administration. The activity of gastric ADH is reduced in women, the elderly, Asian individuals, the fasting state, chronic alcoholism and after gastrectomy. The effect is only present with small (or = 0.3 g/kg) alcohol doses and with a high alcohol concentration. In a number of studies, cimetidine in therapeutic doses over 7 days produced a significant increase in the AUC and in the peak plasma concentration after administration of alcohol 0.15 and 0.30 g/kg. This was related to an inhibition of gastric ADH activity, as shown by in vitro studies. Ranitidine inhibited gastric ADH to a similar extent on a molar basis, but its effect on alcohol levels in vivo was less constant in various studies. Nizatidine also reduced gastric alcohol first-pass metabolism, but famotidine and roxatidine did not show this effect. In other studies, H2-receptor antagonists did not change AUC and peak alcohol concentration. The controversy is not easy to resolve, since a number of the positive studies did not use a placebo-controlled, randomised, crossover design, while some of the negative studies did not exclude habitual alcohol consumers and included Oriental volunteers, although both groups have been shown to lack significant gastric ADH activity. In this case, when first-pass metabolism of alcohol does not exist, this by definition cannot be abolished by H2-antagonists. The inclusion of oral and intravenous dosage data of alcohol is mandatory to positively identify first-pass metabolism in any individuals. The significance of the effect of H2-antagonists on blood alcohol concentrations is minor. It only occurs in young, male, nonalcoholic, non-Asian individuals, and alcohol must be given in a small (social) dose, in a high concentration, and after meals. An increase in alcohol levels in predisposed patients during treatment with some H2-antagonists cannot be excluded, although the likelihood is small. Furthermore, carefully designed studies are needed to clarify fully the significance of this interaction.

In a prospective trial 37 duodenal ulcer patients were treated daily with 1 g cimetidine. Personal and clinical data were obtained for all patients, acid secretion studies performed before and during treatment, and pharmacokinetic parameters of cimetidine determined. The healing rate after 4 weeks was 64.9% (24 patients). Non-Responders included a higher proportion of smokers, patients with a history of ulcer and previous treatment with H2-receptor antagonists than Responders. Basal acid output (BAO) and peak acid output (PAO) values were not different between the two groups, nor was the reduction of BAO and PAO under cimetidine. However, more Responders had complete suppression of BAO than Non-Responders. A correlation existed in both groups between cimetidine plasma concentration and PAO suppression but not with BAO suppression. Regular drug intake (compliance) was found in about 90% in both groups. Cimetidine bioavailability parameters were identical in both groups, but Non-Responders had a higher peak concentration and a shorter time of peak concentration. Discriminant analysis enabled a prediction of treatment response in 89.2% of the patients by using five factors: time of peak concentration of cimetidine, previous H2-receptor-antagonist treatment, peak concentration, smoking, and alcohol use. Prediction of treatment response is increased by use of drug related variables.

The pharmacokinetics of cimetidine (10 mg/kg) were investigated in 11 children following an oral dose and in 9 children following an intravenous dose. The children ranged in age from 4-13 years and were undergoing radiology for upper gastrointestinal tract pain. Compared with a group of adults, the children had a higher total body clearance (11.6 +/- 3.4 versus 7.0 +/- 2.5 ml/min per kg; P less than 0.005), a larger apparent volume of distribution (1.24 +/- 0.40 versus 0.80 +/- 0.24 l/kg; P less than 0.005) and a shorter elimination half-life (83 +/- 26 versus 122 +/- 16 min; P less than 0.001) of cimetidine. Renal clearance in children comprised 70% of total body clearance, more than double that of adults (9.0 +/- 1.9 versus 4.2 +/- 2.1 ml/min per kg; P less than 0.001). The area under the cimetidine plasma concentration: time curve after the oral dose was on average 42% in children compared with adults. The mechanism for the increased elimination of cimetidine in children is suggested to be an increase in the renal tubular secretory transport of cimetidine in the kidney. A statistically significant negative correlation was observed between age and cimetidine renal clearance. A cimetidine dosage regimen of approximately 30 mg/kg per day in three to four divided doses would be an appropriate dose in children.

The pharmacokinetics and bioavailability of cimetidine after 200 mg given intravenously and orally was studied in 6 gastric and 6 duodenal ulcer patients aged between 28 and 64 years. There were no differences in any of the pharmacokinetic parameters between the two ulcer groups, but there was considerable variation which was mainly age-related. Bioavailability was not complete, but was about 60% based on the plasma concentration data. The volume of distribution at steady-state was about 80% of body weight, and the plasma clearance value of 495 ml/min was mainly due to renal clearance (293 ml/min). The elimination half-life was approximately 2 hours. These pharmacokinetic parameters together with the percentage of dose excreted unchanged in urine following intravenous administration were all highly age correlated; all decreasing with age except the elimination half-life which increased with age. Of clinical importance is the finding that the time for which the plasma concentration exceeded 0.5 microgram/ml following oral administration was also highly age-dependent, increasing by more than 2-fold in the elderly (53 to 64y) compared with the younger (28 to 45y) patients.

In a randomized double-blind multicenter trial, 15 outpatients with endoscopically proved anastomotic ulceration after Billroth I or Billroth II partial gastrectomy received cimetidine, 1 g daily over eight weeks, or a placebo. All patients also received antacid. The ulcer healed completely in all seven cimetidine-treated patients and in one of the eight placebo-treated patients (P

1 The pharmacokinetics and bioavailability of cimetidine were studied after 200 mg oral and intravenous doses in 14 patients with liver cirrhosis, and results were compared to a control group of 12 ulcer patients. 2 In cirrhotic patients, the volume of the central compartment (0.41 +/- 0.06 v 0.19 +/- 0.09 1/kg) and the volume of distribution at steady-state (1.02 +/- 0.17 v 0.80 +/- 0.24 1/kg) were significantly increased. No differences were observed in the area volume of distribution, the total systemic plasma clearance and renal clearance. The non-renal clearance was significantly decreased from 191 +/- 46 to 123 +/- 102 ml/min. 3 The bioavailability of cimetidine (area method) was significantly increased from 60 +/- 23% to 77 /+- 18% in the cirrhotic patients. Also increased was the time during which plasma levels exceeded 0.5 microgram/ml. 4 Urinary excretion of cimetidine was increased in liver cirrhosis by 32% after intravenous and by 36% after oral administration, while the amount of the sulphoxide metabolite decreased accordingly. Creatinine clearance in the cirrhotic patients was highly correlated with the renal clearance of cimetidine as well as its total plasma clearance.

The pharmacokinetics of a single 300-mg oral and intravenous and 14 daily 300-mg oral doses of phenytoin were studied in 6 healthy volunteers. The mean plasma elimination t1/2 was the same following intravenous (16.8 +/- 1.3 hr) and oral (17.1 +/- 1.5 hr) doses of phenytoin; however, following chronic oral administration, the t1/2 increased to 18.9 +/- 1.5 hr (p less than 0.05). The absolute bioavailability of an oral dosage form (Dilantin Kapseals) varied from 57.7 to 85.6% when based on the relationship between the corresponding single dose areas under the curve (AUCs). When based on the comparison of the AUC for multiple oral dosing with the single iv dose area, average bioavailability was 85.9% (71.8 to 106.3). Since the variation in the bioavailability and elimination of phenytoin does not allow accurate prediction of the steady-state plasma concentration, monitoring plasma levels may be of special importance.

Since hypolipidaemic drugs are widely used, despite the still unanswered question whether lowering of plasma lipids has a protective effect on the development of atherosclerosis, discussion of the clinical pharmacokinetics of the main representatives of this group of drugs is warranted. Clofibrate is quantitatively transformed to its active metabolite, chlorophenoxyisobutyric acid (CPIB), immediately after oral administration. Absorption of CPIB is complete, but relatively slow with peak concentrations being attained 2 to 6 hours after the dose. The apparent volume of distribution is between 6 and 12 litres; plasma protein binding is higher than 90 %, but is reduced in the nephrotic syndrome, in renal failure, and in cirrhosis. The elimination half-life of CPIB ranges between 10 and 25 hours, is shorter in patients with the nephrotic syndrome, but is prolonged in renal failure in close correlation with the degree of renal impairment. The plasma clearance of the total drug (mean of 7ml/min) appears to be increased in the nephrotic syndrome, but is decreased in renal failure and is unchanged in liver cirrhosis. Clearance of the unbound drug (mean of 240ml/min) is markedly reduced in renal failure, but is also reduced in liver cirrhosis. No pharmacokinetic changes are observed in acute hepatitis. Urinary excretion of CPIB is normally 10 to 15% of the dose; excretion is reduced in renal failure, but is unaffected in the nephrotic syndrome and in liver cirrhosis. Nicotinic acid is rapidly absorbed with peak concentrations being attained after 45 minutes. The systemic availability is about 90 %. Accumulation of the drug is reported in red blood cells, but no information is available on its distribution and on its plasma protein binding. The plasma elimination half-life is about 45 minutes. One third of an oral dose is excreted in urine unchanged. With pharmacological doses the major metabolite is nicotinuric acid; other metabolites being N-methyl-nicotinamide, 2-pyridone, and 4-pyridone, respectively. A measurable pharmacological effect is achieved with plasma concentrations of 0.1 to 0.2μg/ml, while a therapeutic range of 0.5 to 1.0μg/ml is suggested. Flushing of the skin is reported to-occur only at the beginning of treatment when the plasma concentration of nicotinic acid increases. Several analogues of nicotinic acid have been developed with the intention of achieving a sustained effect by a gradual in vivo liberation of nicotinic acid. Cholestyramine is not absorbed from the gastrointestinal tract. As it is an anion exchange resin it may interfere with the absorption of a number of drugs by binding them to the resin. β-Sitosterol absorption is normally less than 5 %, but has been 25% in 2 sisters, so that a genetically determined influence on absorption is assumed. Dextrothyroxine possesses only a small fraction of the hypermetabolic activity of its levoisomer. Absorption is between 40 and 50%, but is decreased in malabsorption syndromes and in some patients with liver cirrhosis. Plasma protein binding is higher than 99 %. The elimination half-life is 6 to 7 days, but is decreased in hyperthyroidism and increased in hypothyroidism. Thyroxine is completely metabolised after oral dosing, une metabolite with pharmacological activity being triiodothyronine.

The correlation between the beta receptor blocking activity of pindolol and plasma level was studied in 8 subjects after a 10-mg oral dose. Exercise tachycardia was markedly reduced over a period of at least 6 hr. Significant effects were recorded 30 min after the drug. For each individual there was a close correlation between log plasma level and beta blockade. The regression lines were parallel as shown by analysis of covariance; the intercepts, however, were significantly different. It can be concluded that there is a correlation between plasma level and beta adrenergic blockade by pindolol, but the data failed to establish in different individuals the blood levels necessary to achieve effective adrenergic blockade.

The introduction of fiberoptic endoscopy has altered the relative importance of ulcer symptoms in the diagnosis of peptic ulcer disease. Interestingly, we now realize that 50% of ulcer patients do not have the classical ulcer symptoms and that 25% of peptic ulcers are asymptomatic. Modern forward-viewing endoscopes of small diameter enable precise diagnosis with little discomfort in 95% of all duodenal ulcer patients. A biopsy is only recommended in rare cases (giant ulcers) because the malignancy rate is only 0.024% in duodenal ulcers. The diagnostic accuracy of endoscopy in detecting gastric ulcer is as high as that for duodenal ulcer, but for this ulcer type it is absolutely necessary to exclude malignancy by obtaining a minimum of six biopsies (four from the ulcer margin and two from the ulcer base), since approximately 10% of all gastric ulcers are actually carcinomas. Whereas in duodenal ulcer repeat endoscopy is seldom necessary, it is mandatory in gastric ulcer since ulcer healing is not proof of a benign ulcer. In experienced hands endoscopy is superior to radiography in duodenal and in gastric ulcer, although there is still a place for radiography as a supplementary investigation or if the patient rejects endoscopy. When selecting patients for treatment of peptic ulcer the following aspects must be considered: natural history of the disease, effectiveness of treatment, and risks and costs of treatment. Treatment goals (relief of symptoms, ulcer healing) can be achieved as far as the acute ulcer is concerned but as yet we have no evidence that we can cure chronic ulcer disease.

infarction is not known. Moreover, the diagnosis of this arrhythmia should not be restricted to instances where delayed repolarization or extreme bradyarrhythmias are present. The therapeutic implications of this finding are unclear. Antiarrhythmic agents which potentially prolong the QT interval may be relatively contraindicated in this setting and the use of bretylium or early ventricular pacing may be preferable.

To evaluated whether knowledge of plasma levels of anti-epileptic drugs has an effect on therapeutic outcome, 127 epileptic outpatients were randomly assigned to two groups (A and B). Plasma levels of group A were reported to the treating physician who attempted to keep the plasma levels within the "therapeutic range." The treating physician was not informed of the results of plasma level determinations of group B. Data from 105 patients were available for assessment at the end of the study year. Therapeutic results of groups A and B were not significantly different. The reduction in seizure frequency was associated with an increase in plasma concentrations of the anti-epileptic drugs. Thus, under the conditions of the study, knowledge of plasma levels of anti-epileptic drugs did not further improve therapeutic results.

The effect of renal failure on the excretion of oral doses of practolol has been studied. The plasma half-life increased up to 6.6 times normal and the cumulative urinary excretion of the drug was reduced. There was a linear correlation between the overall elimination rate constant of practolol and inulin and creatinine clearances. A linear correlation was also found between the renal clearances of practolol and inulin. The dose of practolol required for maintenance therapy should be reduced in patients with impaired renal function.

In a double-blind multicenter trial, 100 patients with active duodenal ulcer were treated with a single nocturnal dose of famotidine 40 mg or ranitidine 300 mg. Antacid tablets were allowed as additional treatment if needed for pain relief. Endoscopy was repeated after two weeks, and again after four weeks if the ulcer had not healed earlier. Two patients in the famotidine group were withdrawn from the study because of non-compliance with the protocol. After two weeks, ulcers in 64 percent of the patients receiving famotidine and 46 percent of the patients receiving ranitidine were healed (p = 0.072). After four weeks, healing rates were 94 percent (famotidine) and 90 percent (ranitidine). Pain relief was rapid in either treatment group, with a tendency for better response during the day in the famotidine group. Mean antacid consumption during the first week was 3.0 tablets (34.5 mmol) in the famotidine group and 4.1 tablets (47.2 mmol) in the ranitidine group. Famotidine provides excellent healing and relief of symptoms in patients with duodenal ulcer disease.

The half-life of antipyrine in plasma was studied In four hyperthyroid and four hypothyroid patients before and after thyroid status returned to normal. The half-life (± S.E.M.) was 7.9 ± 1.0 hours In hyperthyroid and 17.3 ± 1.1 hours in hypothyroid patients. After correction of the abnormal thyroid state the half-life values of both groups (12.3 ± 0.7 and 12.0 ± 0.5 hours) were within the normal range. These results suggest that abnormalities of thyroid function can markedly influence human metabolism of some drugs. (N Engl J Med 290:1040–1042, 1974)

1. β-Receptor-blocking drugs are rapidly and completely absorbed after oral administration. Systemic availability is nevertheless incomplete for propranolol, alprenolol and oxprenolol, owing to ‘first-pass’ extraction by the liver. 2. Plasma half-life is between 2 and 4 h, except for sotalol (10–12 h). Plasma elimination of propranolol is reduced with decreased liver blood flow, observed in congestive heart failure or during chronic propranolol therapy itself. 3. β-Receptor blockade is usually achieved in these concentration ranges: propranolol and alprenolol, 50–100 ng/ml; oxprenolol, 500–1000 ng/ml; pindolol, 10–30 ng/ml; sotalol, 2–6 μg/ml. Higher concentrations are often found with high doses administered to hypertensive patients.

Cimetidine is the first histamine H2-receptor antagonist with wide clinical application. It is a weak base and a highly water-soluble compound which can be measured in biological fluids by a number of high-pressure liquid chromatographic methods. Following intravenous administration, the plasma concentration profile follows multicompartmental characteristics. The total systemic clearance is high (500 to 600 ml/min) and is mainly determined by renal clearance. The volume of distribution (Vd beta or Vdss) is of the order of 1 L/kg and this about equals bodyweight. Elimination half-life is approximately 2 hours. Following oral administration of cimetidine, 2 plasma concentration peaks are frequently observed, probably due to discontinuous absorption in the intestine. The absolute bioavailability in healthy subjects is about 60%. In patients with peptic ulcer disease, bioavailability is around 70%, but the variation is much greater than in healthy subjects. Absorption and clearance of cimetidine are linear after 200 and 800mg doses. Mean steady-state plasma concentrations on a standard 1000mg daily dose are 1.0 microgram/ml (range 0.64-1.64 micrograms/ml) and are reproducible after treatment periods of up to 2 years. When taken with food, the extent of absorption is unaltered, but a delay occurs and only 1 peak in the plasma concentration curve is apparent. Partial gastrectomy (Billroth I, II) causes an increase in systemic availability of cimetidine by an unclear mechanism. Distribution of cimetidine leads to extensive uptake into kidney, lung and muscle tissues. It distributes into the cerebrospinal fluid (CSF) at a ratio of 0.1 to 0.2 compared with plasma. The mean saliva to plasma ratio is 0.2 (range 0.1-0.55). Plasma protein binding is 20%, and there is no relevant effect of changes in binding on the pharmacokinetics of cimetidine. Uptake of cimetidine into red blood cells leads to concentrations equal to those in plasma. Between 50 and 80% of the dose administered intravenously is recovered in urine as unchanged cimetidine. This fraction is less after oral doses, but is independent of the amount of the dose. In ulcer patients, 40% is recovered unchanged in urine after oral administration. Biliary excretion of cimetidine accounts for only 2% of the dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Gastric acid inhibitory effects and kinetics of oxmetidine, a new histamine H2-receptor antagonist, were examined in five patients with duodenal ulcer disease. A constant intravenous infusion of impromidine was used to stimulate gastric acid secretion for 6 hr. Oxmetidine was then given in a 28-mg IV infusion and a 200-mg oral solution. The maximum inhibition of gastric acid output was, on average, 77% after infusion and 92% after oral doses, with similar values for volume inhibition. Mean overall percent inhibition of acid output, volume, and H+ concentration was 22%, 8%, and 15% for the intravenous dose and 51%, 33%, and 29% for the oral dose. The effect lasted for 3 hr after the intravenous dose and for 5 hr after the oral dose. Mean values for systemic clearance and half-life were 161 ml/min and 2.3 hr. An average of 4.3% of the dose was recovered in urine as unchanged drug and 27% was recovered as a glucuronide metabolite. Mean bioavailability was 36%. Plasma concentration for 50% inhibition of acid output was 0.50 μg/ml, indicating that oxmetidine is 2.5 times as potent as cimetidine. No adverse effects were noted during the study. Clinical Pharmacology and Therapeutics (1982) 31, 501–507; doi:10.1038/clpt.1982.67

The disposition of clofibrate over 96 hours was observed following single oral dose in six patients with acute viral hepatitis, six patients with liver cirrhosis, seven patients with renal insufficiency, and six control subjects. No parameter of the disposition of CPIB (active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the non-protein bound drug was reduced (115 vs. 243 ml×min−1), plasma protein binding was reduced (92.8 vs. 97.2 percent), and the apparent volume of distribution was increased (0.20 vs. 0.141×kg−1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml×min−1) and plasma clearance of the unbound drug (81 vs. 243 ml×min−1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.