Search

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.

Previous studies have shown that organic bases, including some drugs, are secreted by renal proximal tubules. The present studies examined the transport of the organic bases cimetidine and procainamide by rabbit proximal straight tubules perfused in vitro. Both drugs were secreted into the tubule lumen. [3H]cimetidine secretion was reduced by quinidine, procainamide, and N-acetylprocainamide. Previous studies showed that cimetidine secretion was reduced by other organic bases. Hypothermia and ouabain inhibited [3H]procainamide secretion as was shown previously for cimetidine secretion. [3H]procainamide secretion was also reduced by quinidine, cimetidine, procainamide, and N-acetylprocainamide but not by probenecid. High concentrations of cimetidine (10(-3) M) had no effect on the rates of fluid or total CO2 absorption. When analyzed in terms of Michaelis-Menten kinetics, the effect of cimetidine on procainamide secretion and procainamide on cimetidine secretion was consistent with competitive inhibition. The results suggest that both cimetidine and procainamide are secreted into the lumen of proximal straight tubules predominately by an organic base transport mechanism. These studies raise the possibility that some of these drugs might compete for a common secretory mechanism in renal tubules and reduce the elimination of each other.

This study tested the hypothesis that cimetidine and ranitidine, the new H2-antagonist, may influence the pharmacokinetics of theophylline administered i.v. at two different doses (3.4 and 6.5 mg/kg body wt.). Twenty hospitalized patients with chronic obstructive lung disease (COLD) and peptic ulcer were administered cimetidine or ranitidine orally for 8 days at the routine doses of 2 X 400 mg/day and 2 X 150 mg/day, respectively. Blood samples were collected over a 10-h period before and after H2-antagonist therapy. Cimetidine significantly reduced theophylline clearance, but increased its half-life and the area under the curve (AUC) (p less than 0.001). Ranitidine, on the contrary, did not show any interaction with these pharmacokinetic parameters. Neither of the H2-blocking agents modified the volume of distribution. Furthermore, the delay in theophylline elimination due to cimetidine was more evident at the higher dose of the xanthic drug; this effect induced remarkable changes in plasma theophylline concentrations. Consequently, pharmacokinetic interaction between cimetidine and theophylline may produce serious clinical problems in the management of patients treated with both drugs concurrently, problems which do not arise with ranitidine.

Fifteen cases of cimetidine-associated mental confusion have recently appeared. To further study this syndrome, we monitored cimetidine serum concentrations in 36 patients and correlated these with changes in mental status. Thirty patients did not change on cimetidine and 6 experienced moderate to severe mental status changes. These 6 patients had both renal and liver dysfunction (p less than 0.05), as well as cimetidine trough concentrations above 1.25 micrograms/ml (p less than 0.05), in close association with mental status changes. The changes in mental status became progressively more severe as trough concentrations rose. Five patients underwent lumbar punctures. The cerebrospinal fluid to serum ratio of 0.24:1 indicates that cimetidine passes the blood-brain barrier, and this raises the possibility that mental status changes are due to blockade of central nervous system histamine H2 receptors. Our studies identify a subgroup at high risk for both elevated troughs and mental confusion. These patients with severe compromise of both renal and hepatic excretory systems must be closely observed and given reduced cimetidine doses if side effects are to be avoided.

1 The absorption and elimination of a single oral dose of 400 mg cimetidine was studied in fourteen fasting patients with impaired renal function. In addition, the dialysance of cimetidine was studied in five patients on haemodialysis. 2 The absorption was somewhat, but clinically insignificantly delayed. A second unexplained peak in the absorption curve was found. 3 First order elimination kinetics were confirmed and the length of time of a cimetidine concentration over 0.5 mg/l could be correlated with creatinine clearance. 4 The magnitude of extra renal elimination was estimated to be approximately one fourth of total cimetidine elimination in normal patients and seemed unaffected by impaired renal function. 5 A dose schedule based on AUC found in the patients in renal failure is suggested. The recommendations for daily oral dose range from 300 mg (at borderline dialysis) to 1000 mg in mild renal failure. The suggested doses will give an average plasma concentration of the same order as seen in patients with normal renal function.

The effect of impaired liver function on the pharmacokinetics of cimetidine was studied in 8 patients with advanced cirrhosis given single doses of 100 mg i.v. and 400 mg p.o. on separate days. Compared to a control group of 10 healthy volunteers, the total renal and nonrenal clearance was significantly reduced in the cirrhotic patients; (total plasma clearance mean +/- SD) 356 +/- 181 vs 789 +/- 262 ml/min (p less than 0.01); renal clearance (Clr) 296 +/- 100 vs 588 +/- 181 ml/min (p less than 0.01) and nonrenal clearance ( Clnr ) 97 +/- 111 vs 205 +/- 89 ml/min (p less than 0.05). Compared to published results for age-matched ulcer patients, both total and nonrenal clearance were lower whereas renal clearance was within the reported normal range. A significant reduction in volume of distribution (Vd beta) was found, from 2.1 +/- 0.1 l/kg in controls to 1.0 +/- 0.4 l/kg, and in the patient group there was a significant correlation between Vd beta and total plasma clearance (r = 0.72, p less than 0.05). Volume of distribution in steady state (Vdss) did not differ from published results in age-matched controls. No significant change in half-life was found. Bioavailability, estimated by AUC-measurement, showed considerable patient variability (21-143%), with a mean of 70 +/- 39%. This was lower than in the controls. In contrast, measurement of urinary excretion showed higher bioavailability in the patients (66 +/- 23 vs 51 +/- 8%). No correlation was found between any of the kinetic parameters and the clinical and laboratory data.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The novel benzthiazole derivative zolantidine (SK&F 95282) is a potent antagonist of histamine at H2-receptors in guinea-pig atrium and rat uterus. Only apparent pA2 values of 7.46 and 7.26 respectively could be calculated since the slopes of the Schild plots were significantly less than unity. 2. Zolantidine is equally potent as an antagonist at histamine H2-receptors in guinea-pig brain. The compound inhibited histamine stimulated adenylate cyclase (pKi 7.3) and dimaprit stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation (approx pA2 7.63), and competed with [3H]-tiotidine binding (pKi 7.17). 3. Zolantidine is at least 30 fold more potent at H2-receptors than at other peripheral and central receptors investigated. 4. Infusion of zolantidine into rats produces a brain concentration greater than the plateau blood concentration (brain/blood ratio 1.45). 5. Zolantidine is thus characterized as a potent selective brain-penetrating H2-receptor antagonist, and will be a valuable pharmacological tool for investigating possible physiological and pathological roles for histamine in the central nervous system.

The H2-antagonist cimetidine is widely employed in biochemical and pharmacological studies of the H2-receptor. These studies include the use of 3H-cimetidine in radioligand binding experiments. Confirming our previous finding as to the unsuitability of this ligand in these types of investigations, we now report data showing the lack of correlation between the displacement of specific 3H-cimetidine binding and histamine stimulated adenylate cyclase activity, and the displacement of specific binding by imidazoles devoid of H2-receptor activity. Results are also presented which question the use of copper ions in 3H-cimetidine binding studies. Our conclusions are discussed in relation to the work carried out by a number of laboratories where 3H-cimetidine is reported to label the H2-receptor.

The bioavailability of p.o. and i.v. cimetidine was studied in 12 patients with compensated liver cirrhosis in a crossover study. Single doses of 200 and 400 mg cimetidine were used for both administration routes. Plasma concentration and urinary recovery were determined by the HPLC method. The pharmacokinetic data observed in these patients do not differ from those of normal subjects and patients. A positive correlation between AUC and cimetidine oral dose was found. Oral bioavailability of cimetidine was about 94% compared to that of the i.v. route. The p.o. dose of 400 mg produced AUC values similar to the i.v. dose of 400 mg. After 400 mg cimetidine p.o. the mean peak plasma level was higher and the time for which plasma levels remained above 0.5 mg/l was longer. There were no significant differences between plasma cimetidine levels after the intravenous administration of 200 and 400 mg. The urinary recovery of cimetidine was significantly higher after intravenous administration independently of the given dose. The pharmacokinetics of cimetidine does not appear to be altered in liver cirrhosis.

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 postabsorptive distribution of cimetidine is described. Assays by high pressure liquid chromatography (HPLC) of postmortem samples of cerebrospinal fluid, serum, and solid tissues were used to determine pharmacokinetic parameters as well as mean tissue: serum concentration (T:S) ratios in seven patients with renal and liver dysfunction. Correlations were calculated between the T:S ratio and the volume of distribution, and between the T:S concentration ratio and the time of sampling after death. The highest T:S ratios occurred in the eliminating organs, the liver and kidneys, and the lowest in fat. As the time of autopsy increased after death, the T:S ratios decreased.

Cimetidine induces reversible dose-related central nervous system (CNS) toxicity. Trough serum concentrations and the development of CNS toxicity correlate. We compared cimetidine kinetics in 12 healthy subjects and 31 patients. Six of the latter had normal renal and liver function, five had renal disease only, 12 had liver disease only, and eight had both renal and liver disease. Postmortem tissue distribution was assessed in 11 patients, and expressed as tissue:serum ratio. Average cimetidine total clearance (ClB) in milliliters per minute for each group was as follows: patients with renal and liver disease (182 +/- 105), renal disease only (193 +/- 24), liver disease only (463 +/- 145), normal patients (510 +/- 93), and healthy subjects (583 +/- 140). Renal function was the major determinant for ClB, and the relationship was described by ClB = 4.2(CCr) + 140, r = 0.87, where CCr is creatinine clearance. Cimetidine clearance was affected little by age. Tissue:serum ratios from highest to lowest were as follows: kidney greater than stomach greater than liver greater than bone greater than brain greater than fat. Central and steady-state distribution volumes were not influenced by age or disease. There was enchanced CNS penetration in liver disease patients; their cerebrospinal fluid (CSF):serum ratio was twice the normal. Our kinetic studies identify patient characteristics likely to result in elevated blood levels, and suggest that the greatest risk of CNS toxicity is in those with liver disease.

The binding of cimetidine to rat liver microsomes in M/15 phosphate buffer, pH 7.9, has been investigated by difference spectroscopy and also by equilibrium partition studies, the latter method providing the more definitive characterization of the interaction in the pharmacologically relevant, low micromolar range of drug concn. In addition, the effect of cimetidine on the rate of dilution-induced displacement of [3H]cimetidine from rat liver microsomes has been used to justify consideration of the binding results in terms of two distinct and independent classes of microsomal site, governed by dissociation constants of 8.3 and 104 microM under the above conditions. By demonstrating unequivocally the existence of the stronger interaction, this investigation has provided an acceptable experimental basis for considering the undesired side effect of cimetidine in concomitant use with a number of other drugs to be the consequence of its inhibition of their monooxygenase-dependent metabolism.

The pharmacokinetics of orally administered cimetidine was studied in 8 healthy subjects before and after 3 weeks of treatment with phenobarbital 100 mg daily, and in a separate study 4 subjects received cimetidine intravenously before and after the administration of phenobarbital. There was no change in the volume of distribution, but total plasma clearance was increased by a mean of 18%, mainly due to a 37% increase of nonrenal clearance. Renal clearance and half-life were not significantly altered. The area under the plasma concentration-time curve after oral administration was significantly (P less than 0.05) reduced by a mean of 15% after phenobarbital treatment. The amount of cimetidine excreted in urine and its sulphoxide metabolite were significantly (P less than 0.05) reduced, on average by 34% and 26%, respectively by phenobarbital treatment. The data indicate that an apparent 20% reduction in the absorption of cimetidine was due to induction of gastrointestinal metabolism of cimetidine, with some contribution also from hepatic metabolism. Reduced absorption per se could not be totally excluded. Although the magnitude of the change was small, the finding of an 11% decrease in the time to achieve an effective plasma level of cimetidine after phenobarbital treatment may contribute to the ineffectiveness of cimetidine in certain patients.

Cimetidine dynamics were studied in six multiple-trauma patients receiving 300 to 600 mg every 6 hr for prevention of stress ulceration. Patients received cimetidine intravenously for a mean duration of 7.8 days. There was a positive correlation between cimetidine serum concentration and gastric pH; the correlation between intragastric cimetidine concentration and gastric pH was stronger. The association between therapeutic efficacy (pH greater than 4) and serum concentration over 1 mcg/ml was significant. The association with gastric cimetidine concentration above 2 mcg/ml was significant.

Ranitidine and cimetidine are competitive antagonists of histamine at H2-receptor sites in the gastric mucosa. Both drugs reduce output of basal and stimulated gastric acid and pepsin secretion in normal healthy subjects and duodenal ulcer patients. Pharmacodynamic and pharmacokinetic differences exist between the drugs, some of which are of clinical significance. Ranitidine is a 6-8 times more potent inhibitor of gastric secretions and also causes a greater reduction in intragastric acidity of nocturnal secretions after usual therapeutic doses. Absorption from the gastrointestinal tract of both drugs is good, with peak plasma concentration occurring approximately 90 minutes after oral administration. Systemic bioavailability is approximately 70% with cimetidine and 50% with ranitidine. Both drugs demonstrate biexponential elimination curves from the plasma after intravenous administration and a bimodal curve after oral administration which is probably the result of enterohepatic recirculation. The elimination half-lives of cimetidine and ranitidine are 1.7-2.1 hours and 2.1-3.1 hours, respectively, with apparent volumes of distribution approximating 50L and 75L, respectively. Both drugs are eliminated, largely unchanged, via the kidneys. Major differences between these agents are found in cimetidine's biological activity at sites other than the gastric H2-receptors. These include: antiandrogenic effects with the appearance of feminizing characteristics in men, especially with large doses, like those used to treat Zollinger-Ellison syndrome; interference with the hepatic P-450 mixed-function oxidase enzyme system, which results in drug interactions with warfarin, phenytoin, theophylline and other drugs; and central nervous system effects characterized by confusion, particularly in elderly patients and those with renal failure. Such side effects have not been directly related to ranitidine treatment and substitution of ranitidine for cimetidine has reportedly provided effective alternative treatment in patients intolerant to cimetidine.

Experiments were conducted to study the transport of the histamine H2-receptor antagonist, cimetidine, in luminal membrane vesicles prepared from rabbit renal cortex. Cimetidine accumulated in the vesicles with time. Cimetidine uptake was sensitive to changes in vesicle size, suggesting that the compound is transported into an osmotically reactive intravesicular space. Its rate of uptake could be described by both a saturable and a nonsaturable process. The Km was 4.6 +/- 4.0 microM and the Vmax was 6.8 +/- 2.3 pmol X s-1 X mg protein-1 (mean +/- SD, n = 4). N1-methylnicotinamide (NMN), cimetidine, cimetidine sulfoxide, and ranitidine inhibited the uptake of cimetidine. Cimetidine uptake in the presence of an outwardly directed proton gradient was enhanced in vesicles preloaded with a higher concentration of unlabeled cimetidine (2.4 X 10(-4) M). An outwardly directed proton gradient enhanced the uptake of cimetidine to values exceeding its equilibrium accumulation. Uptake stimulated in this way could be inhibited by the cation, NMN, the bases, ranitidine, and cimetidine sulfoxide, and interestingly, by the anion, probenecid. The effect of probenecid did not appear to be due to nonspecific effects on membrane binding, membrane potential, or vesicle size. These data are consistent with data obtained in isolated perfused proximal tubules, demonstrating that probenecid inhibits cimetidine transport. The data in this study suggest that the effect of probenecid on cimetidine transport specifically involves the transporter in the luminal membrane.

The degradation of nitrosocimetidine (NC) and its mechanism were found to be strongly dependent upon pH by monitoring NC and its degradation products by high-performance liquid chromatography (HPLC). NC was relatively stable at neutral pH, but it degraded rapidly under both acidic and alkaline conditions. In a strongly acidic solution, the degradation was shown to be entirely by denitrosation, but under alkaline conditions scarcely any denitrosation was observed and various other degradation products were found. At neutral pH, both these degradation mechanisms were observed. In neutral solution, the presence of thiol compounds greatly shortened the half life of NC, and enhanced its denitrosation. The high degradation rate in acidic solution, the strong influence of thiol groups, and the preference of denitrosation at pH 0.3-5 can explain the discrepancy between the in vitro genotoxicity and the lack of carcinogenicity of NC.

The placental transfer and renal elimination of cimetidine were studied at steady state in near-term pregnant sheep. In seven nonanesthetized sheep, maternal dosage produced mean steady-state plasma concentrations of 776 +/- 217 ng/ml in the mother and 32 +/- 15 ng/ml in the fetus. Total cimetidine clearance was 41.63 +/- 9.10 liters/hr in the mother, whereas renal cimetidine clearance was 29.96 +/- 15.74 liters/hr in the mother and 1.53 +/- 0.48 liters/hr in the fetus. The mean ratio of cimetidine/creatinine renal clearance was similar in fetus and adult and was considerably greater than unity (7.5 and 7.1, respectively), suggesting active tubular secretion of equal efficiency in both. Fetal dosage in six of the nonanesthetized preparations reversed the maternal-fetal plasma cimetidine concentration gradient (fetal plasma = 16,895 +/- 5,507 ng/ml; maternal plasma = 513 +/- 184 ng/ml). At these very high fetal plasma concentrations, the mean fetal cimetidine/creatinine clearance ratio (2.1) was significantly lower, consistent with the saturation of an active renal tubular secretory process. In four anesthetized sheep, both maternal and fetal renal cimetidine clearances (9.83 +/- 5.39 and 0.32 +/- 0.14 liters/hr, respectively) were 70 to 80% lower than in nonanesthetized sheep. Umbilical venous and arterial cimetidine concentrations were similar (42 +/- 11 and 43 +/- 11 ng/ml, P greater than .05) but substantially less than the maternal plasma concentration (1535 +/- 500 ng/ml). Thus, the principal gradient occurs across the placenta rather than across the fetus. This suggests that, although the fetal kidney can extract cimetidine efficiently, low fetal drug concentrations are primarily due to the placenta and not to fetal drug elimination.

The effects of the H2-receptor antagonists cimetidine, ranitidine, mifentidine and three analogues of mifentidine, were studied on the spontaneously beating right atrium (H2-antagonism) and membranes of the cerebral cortex (displacement of 3H-tiotidine), both obtained from the male guinea-pig. The choice of these compounds was based on preliminary experiments in which some mifentidine analogues were shown to displace tiotidine from the H2-receptor in a deviant manner. In the present study we investigated the relation between pharmacological response and receptor binding, also testing the degree of irreversible antagonism of these compounds in the atrium (functional) and cerebral cortex (binding) model. Our data indicate that a relation between the two different approaches for measuring the effect on the H2-receptor can be found, although some differences emerged as well.

Unlabelled: By means of a Latin square design, the effect of antacid alone and in combination with cimetidine on a 24-hour intragastric hydrogen ion (H+) activity and serum gastrin profiles was studied in eight patients with duodenal ulcer. Antacid given seven times a day (one and three hours after meals and at bedtime) combined with 600 mg BID of cimetidine (C + A7) achieved greater suppression of H+ after breakfast, overnight, and over the 24-hour period than did antacid alone seven times daily (A7). Antacid given four times a day (one and three hours after lunch and after supper) combined with cimetidine BID (C + A4) maintained the neutralizing capacity during this time, but was less effective than the C + A7 regimen. However, C + A4 produced more suppression of nocturnal H+ than did A7. A higher percentage of the readings at or above pH 4.0 were obtained with C + A7 than with A7 or C + A4. A greater postprandial integrated gastrin response was obtained with all active treatments as compared with a placebo regimen. The mean peak cimetidine concentration (Cmax) was higher but the time to peak (Tmax) was shorter after the morning than after the evening dose. The area under the cimetidine concentration-time curve and the Cmax and Tmax values after the morning and evening doses of cimetidine were not affected by the coadministration of antacid., In Conclusion: (1) combination therapy of cimetidine plus antacid is more effective than antacid alone in the reduction of intragastric H+; (2) antacid alone fails to suppress the overnight intragastric acidity; and (3) antacid given concurrently with cimetidine does not interfere with pharmacokinetic determinants of plasma cimetidine concentration.

The intragastric host-mediated assay (h.m.a.) was devised and carried out with a view to assessing the formation of direct mutagens in the gastrointestinal tract of mammals. The h.m.a. consists in the injection of nitrosable compounds, NaNO2 and cells of the yeast S. pombe, by gavage into the animals' stomachs and in the recovery of the target cells from the faeces for mutation-induction analysis. Methylurea was chosen as a model nitrosable compound, and the effects of nitrosation modulators such as ascorbic acid and thiocyanate were studied. Cimetidine, a drug nitrosable in vitro, was tested with the system. Positive results were obtained only at very large doses and in artificially produced low pH. The new host-mediated assay seems to be efficient in revealing the formation, in vivo, of direct, short-living mutagens.

Theophylline and warfarin are two drugs whose interactions with cimetidine may have clinically significant effects. Therefore, recent efficacy studies comparing cimetidine 800 mg at bedtime (HS) with 300 mg QID included studies of interactions between cimetidine and these agents. Thirty healthy men were stratified into three age groups: 18 to 35, 36 to 53, and 54 to 70 years and were given 300 mg QID of anhydrous theophylline sustained-action tablets. When steady state was reached (nine days), cimetidine was begun concomitantly in a dosage of 300 mg QID or 800 mg HS for ten days. Three days after cimetidine was started, morning and evening trough theophylline serum levels were monitored. The area under the theophylline serum level-time curve (AUC) was determined on days 5 and 10 of the cimetidine regimen. Upon discontinuation of cimetidine, morning and evening trough serum theophylline levels were measured to determine when all subjects had returned to precimetidine steady-state conditions. A new baseline AUC was then obtained and concomitant administration of the alternate cimetidine regimen was started. Serum theophylline levels were measured as with the first cimetidine regimen. Theophylline was continued for an additional ten days with monitoring of trough levels, after the second cimetidine regimen was completed. AUC was measured after precimetidine steady-state conditions were reached. Steady-state theophylline levels were increased less by the 800-mg HS cimetidine regimen than by the 300-mg QID regimen. Although both regimens significantly (P less than 0.05) increased the theophylline AUC and maximum serum concentration (Cmax) in all age groups, the effect of cimetidine 800 mg HS was significantly less for all subject data combined and particularly for the oldest groups of subjects, indicating that the theophylline-cimetidine interaction is age-related. New theophylline steady-state levels were achieved by day 5 of concomitant cimetidine administration, and precimetidine theophylline serum trough levels, Cmax, and AUC were observed five days after discontinuation of both cimetidine regimens. The effects of the same two cimetidine regimens on the pharmacodynamics and pharmacokinetics of warfarin were also evaluated in 25 patients stabilized on anticoagulant therapy. The preliminary data indicate that patients with a baseline prothrombin time ratio (PTR) of less than 2.0 would not be expected to exceed a PTR greater than 2.5 after two weeks of concomitant administration of cimetidine at either dosage.(ABSTRACT TRUNCATED AT 400 WORDS)

Eleven patients with ascitic cirrhosis and eleven patients without liver disease received 200 mg of cimetidine orally and intravenously. Plasma concentrations of cimetidine were analysed by high pressure liquid chromatography. No differences were observed in cimetidine half-life (2.53 +/- 0.63 and 2.33 +/- 0.40 h) between the two groups. Cimetidine clearance was diminished by about 30 p 100 in cirrhotic patients (0.426 +/- 0.138 vs. 0.649 +/- 0.163 l/h/kg). The apparent volume of distribution was also significantly diminished (1.50 +/- 0.44 vs. 2.14 +/- 0.55 l/kg) in patients with cirrhosis and ascites.

The influence of cimetidine coadministration, 300 mg every 6 hours, on the kinetics of single oral doses of oxazepam (30 mg), lorazepam (2 mg), and flurazepam (30 mg) was evaluated in healthy volunteers. Cimetidine had no significant effect on the peak plasma concentration or the time of peak concentration for either oxazepam, lorazepam, or desalkylflurazepam (formed from flurazepam). Cimetidine likewise did not alter the elimination half-life of oxazepam (9.4 hours) or lorazepam (11.6 hours), and did not change total AUC for lorazepam. Oxazepam AUC was increased an average of 10 per cent by cimetidine (P less than 0.02). In contrast, cimetidine prolonged desalkylflurazepam elimination half-life (141 vs. 94 hours, P less than 0.1) and increased AUC an average of 65 per cent (P less than 0.05). Thus, cimetidine has little or no influence on the absorption or disposition of oxazepam and lorazepam, two benzodiazepines biotransformed by glucuronide conjugation. However, cimetidine slows the elimination of flurazepam's metabolite, desalkylflurazepam, which is biotransformed by oxidation.

The pharmacokinetics of cimetidine after an oral dose of 400 mg were measured in 18 patients with duodenal ulcer, 9 refractory and 9 responders. The peak plasma concentration of cimetidine (2.13 +/- 0.17 micrograms/ml vs 1.43 +/- 0.04 micrograms/ml), the area under the plasma concentration curve (A.U.C.) between 0 to 8 hours after cimetidine (8.49 +/- 0.29 micrograms/ml/h vs 5.83 +/- 0.25 micrograms/ml/h), and the time span in which cimetidine was above 0.5 micrograms/ml (I.C.50) (401 +/- 8.86 min vs 296 +/- 20 min) were all found to be greater in responding patients than in non-responders to the therapy. No differences were detectable between the two groups in urinary excretion, T 1/2 of cimetidine or percentage inhibition (1%) of maximal pentagastrin-stimulated acid output (MAO). The results indicate that clinical healing of duodenal ulcer after cimetidine is related principally to the drug's pharmacokinetics, i.e. to its absorption from the small bowel, and that some other therapeutic approaches might be tried before surgery in cases of duodenal ulcer refractory to cimetidine.

When safflower oil (triglyceride) was consumed without pancreatic enzymes by children with cystic fibrosis (CF), there was no rise in mean plasma linoleic acid levels over the next 4 h. When linoleic acid monoglyceride (LAM) was consumed, the increase in plasma linoleic acid levels was significantly greater than for safflower oil at 2 (p less than 0.02), 3 (p less than 0.01), and 4 h (p less than 0.01). When free fatty acid (hydrolyzed safflower oil) was ingested, there was almost no increase in plasma linoleic acid levels in CF or control children. The absorption of linoleic acid from triglyceride, but not from LAM, was greater when the CF children also took pancreatic enzymes. Three children with CF had greater increases in plasma linoleic acid levels following ingestion of safflower oil when they took antacid and cimetidine with their pancreatic capsules, compared to when they only took the pancreatic capsules.

A model is developed to estimate the renal tubular secretory parameters by the multiple indicator dilution (MID) technique. The model allows the calculation of influx (from plasma space to tubular cell), efflux (from tubular cell to plasma space) and sequestration (from tubular cell to luminal side) rate constants. A program using the MID-statistical analysis with least squares fitting (SALS) system for the estimation of these parameters is presented. A trapezoid rule and a non-linear least squares regression were used to carry out definite integrals of cubic spline function and least squares fitting, respectively. The system presented seems to be useful for the precise and rapid estimation of the tubular secretory rate constants.

The interactive effects of the coadministration of steady-state cimetidine and single-dose pentopril, an angiotensin converting enzyme inhibitor, on the pharmacokinetic disposition of each other were studied in humans. Cimetidine reduced the clearance of pentopril by 11 to 14%. This reduction in clearance was shown to be caused by a reduction in liver blood flow probably mediated through H2 receptor blockade. Meanwhile pentopril induced the oral clearance of cimetidine by 21%, presumably by a reduction in the bioavailable fraction of cimetidine. The mechanism of this interaction is unknown.