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The purpose of this study was to evaluate effects of antacids on predicted steady-state concentrations of cimetidine. Ten healthy volunteers received in random order one week apart, cimetidine and cimetidine and antacid suspension. Blood was obtained at specified times and analyzed for cimetidine. Bioavailability was assessed by comparison of peak concentration, time to peak concentration, area under the curve, and time spent over 0.5 micrograms/ml. Single-dose data were extrapolated to steady-state using computer simulation. Concurrent administration of antacid suspension reduced parameters of bioavailability approximately 30%. When steady-state conditions were simulated, concentrations of cimetidine greater than or equal to 0.5 micrograms/ml were maintained for the entire dosing interval in seven of 10 subjects. These data suggest that temporal separation of cimetidine and antacid suspension may be unnecessary.

The effect of cimetidine on the pharmacokinetics of theophylline was evaluated. Twelve healthy men volunteers participated in this two-way crossover study. Six subjects were initially treated with theophylline (control), and six were treated with cimetidine and theophylline (cimetidine). Sixteen days after the start of the first phase, the subjects were crossed over. Aminophylline equivalent to 2 mg/kg theophylline was dissolved in 100 ml 5% dextrose injection and infused into an antecubital or forearm vein over a 20-minute period. Cimetidine was ingested in 300-mg doses every six hours beginning 48 hours before the theophylline infusion and continued until 48 hours after the infusion. Blood samples were collected periodically for 48 hours, and serum theophylline concentrations were determined by liquid chromatography. Theophylline concentration versus time data were computer fitted to a biexponential equation. Total theophylline clearance (CLtot), apparent volume of distribution (V), and elimination half-life (t 1/2 beta) were calculated. Semilogarithmic plots of theophylline disappearance showed a decrease during cimetidine treatment. Mean theophylline t 1/2 beta increased significantly during cimetidine treatment from 5.9 +/- 1.0 to 7.3 +/- 1.5 hr, and CLtot decreased significantly from 0.065 +/- 0.010 to 0.049 +/- 0.012 liter/hr/kg. Mean V was unchanged. Two subjects failed to exhibit decreased theophylline clearances, and theophylline clearance increased in another subject. Cimetidine was found to slow the clearance of theophylline and to extend its half-life. Daily doses of theophylline may require adjustment in patients requiring the coadministration of cimetidine. Cimetidine should be added with caution, and serum theophylline concentrations should be monitored accordingly.

The Kd-values of some histamine H2-active compounds, obtained from radio-ligand-binding studies on a homogenate of the guinea-pig cerebral cortex with 3H-tiotidine as the labelled H2-ligand, were compared with the pA2/pD2-value of these compounds on the guinea-pig right atrium and guinea-pig isolated gastric fundus. A good correlation was found between the pKd of the H2-antagonists and their pA2 on the guinea-pig right atrium. A much poorer correlation however was obtained between the pKd of the agonists on the cerebral cortex and their pD2-values on the guinea-pig right atrium and the gastric fundus. This poor correlation between true affinity and H2-activity of the agonists might be explained by spare receptors as a much better correlation was obtained between pKd and pD2 of partial agonists.

The two imidazole histamine H2-receptor antagonists etintidine and cimetidine interact with the rat liver microsomal cytochrome P-450. From type II spectral changes follows that the affinity of rat liver microsomal preparations for etintidine is about 5 times as high as for cimetidine when comparing both high and low affinity binding sites. After pretreatment with phenobarbital etintidine inhibited benzphetamine N-demethylation competitively (app. Ki: 4.0 mmol/l). Cimetidine inhibited benzphetamine N-demethylation in the same range. After pretreatment with phenobarbital both drugs inhibited the oxidation of benzo(a)pyrene for which etintidine showed a higher inhibitory potency than cimetidine. However, this oxidation could not be inhibited when microsomes of 5,6-benzoflavone pretreated rats were used. After pretreatment with 5,6-benzoflavone only etintidine but not cimetidine inhibited the O-deethylation of ethoxyresorufin competitively (app. Ki: 0.2 mmol/l). Etintidine and cimetidine were metabolized by rat liver microsomes to their corresponding sulphoxides. In conclusion, etintidine may cause mainly the same drug interactions as cimetidine but seems to be a more potent inhibitor.

The use of the electrical circuit simulation program SPICE2 for performing digital computer simulations of linear and non-linear pharmacokinetic-pharmacodynamic models is described. SPICE2 utilizes the principles of network thermodynamics (thermodynamics of electrical circuits). These principles dictate analogy between the conservation laws of chemical reactions and mass transport and Kirchhoff's laws of current and voltage balance, and also prove that Fick's law of diffusion is isomorphous with the conductance form of Ohm's law. Detailed descriptions of program inputs, formats, and options for simulation of linear and non-linear pharmacokinetic-pharmacodynamic systems are provided, with appropriate examples. Single as well as multiple dose simulations (accumulation kinetics and dynamics) are discussed. The advantages of SPICE2 over other available simulation packages, including user-friendliness, ease of operation, versatility, power, and the economy of time and effort afforded, are emphasized. The educational value of SPICE2 as a highly versatile tool for teaching both fundamental and complex pharmacokinetic-pharmacodynamic concepts, as well as its routine usage in elucidating complex research problems, are also discussed.

The interaction of 4(5)-[2-(4-azido-2-nitroanilino)ethyl]imidazole (AAH), a photolabile histamine receptor antagonist, with the binding of histamine, mepyramine, and tiotidine to guinea pig cerebral cortical membranes was examined to evaluate the specificity of AAH for histamine H1 and H2 receptors. Saturable, specific binding of [3H]histamine, [3H]mepyramine, and [3H]tiotidine to the membranes was observed. Competition assays were used to assess the relative affinity of AAH for H1- and H2-receptors. The rank order of IC50 values obtained was (most to least potent) (i) for competing with [3H]histamine binding: histamine greater than AAH much greater than mepyramine approximately equal to tiotidine; (ii) for competing with [3H]mepyramine binding: mepyramine much greater than AAH greater than histamine greater than tiotidine; and (III) for competing with [3H]tiotidine binding: tiotidine much greater than mepyramine greater than histamine approximately equal to AAH. The affinity of AAH for H1 receptors was ca. 14-fold greater than for H2 receptors. These findings support previous evidence obtained in isolated smooth muscle preparations that AAH shows H1-receptor selectivity as an antagonist.

Cimetidine given orally without food after an overnight fast produces a blood concentration curve with a pronounced second peak that does not appear after parenteral administration or when the drug is taken with food. The following interpretation of this kinetic phenomenon is proposed: 1. The drug cumulates in a tissue or organ that is well perfused in the first-pass transfer. 2. The hepatic parenchymal tissue and the bile phase are the most likely storage areas. 3. The high capacity of the cumulation may be due to the formation of conjugates or other modifications of the drug with a pronounced affinity for the hepatic-biliary system. 4. The rate of cumulation is much higher in the first-pass transfer than from the systemic circulation, possibly due to the difference in the drug concentrations and the conjugation rate. 5. The cumulation appears to occur by a competitive process. 6. Absorbed elements of food seem to compete in this process. 7. The second peak apparently is the result of a rapid release of drug and bioreversible drug compounds from the hepatic-biliary system with subsequent reabsorption. 8. This release may occur spontaneously but appears to be triggered by food intake. A pharmacokinetic model constructed according to this interpretation showed good agreement with data from oral, intravenous, and intramuscular administration. The special problems associated with the evaluation of bioavailability in the presence of reabsorption are discussed.

1. Sulphoxidation of cimetidine and etintidine was investigated by in vitro assays with liver microsomes from untreated 5,6-benzoflavone- and phenobarbital-pretreated rats as well as with human liver microsomes. The formation rate of cimetidine sulphoxide and etintidine sulphoxide with liver microsomes of normal or pretreated rats reached to 1.1 and 0.9 nmol/min mg microsomal protein, respectively. 2. Inhibition experiments with carbon monoxide and n-octylamine indicated that this sulphoxidation is catalyzed by cytochrome(s) P-450, whereas flavin-containing monooxygenase and/or non-enzymatic reactions (via peroxides) seems not to be involved: no inhibition was observed by methimazole, N,N-dimethylaniline, preheating or glutathione and EDTA. 3. With human liver microsomes the cytochrome P-450-dependent sulphoxidation accounted for no more than 40% of the total oxidation.

In 35 patients (ages 20 to 86 yr) receiving cimetidine therapeutically two serum samples and all urine formed in the interim were collected for analysis of cimetidine by high-pressure liquid chromatography and for creatinine. Cimetidine clearance decreased with age. The extrapolated 6-hr serum concentration of cimetidine per unit dose, after intravenous cimetidine, increased with age of the patients. The ratio of cimetidine clearance to creatinine clearance (Rc) averaged 4.8 +/- 2.0, indicating net tubular secretion for cimetidine. Rc seemed to be independent of age and decreased with increasing serum concentration of cimetidine, suggesting that secretion of cimetidine is a saturable process. There was only one case of dementia possibly due to cimetidine (with a drug level of 1.9 microgram/ml 6 hr after a dose) in a group of 13 patients without liver or kidney disease who had cimetidine levels above 1.25 microgram/ml. Thus, high cimetidine levels alone do not always induce dementia.

The O-deethylation of 7-ethoxycoumarin was inhibited in a mixed type manner by cimetidine in vitro and in microsomes isolated from rats treated with cimetidine in vivo. It was found that the inhibition was even greater if cimetidine was preincubated with the microsomal suspension in the presence of an NADPH-generating system prior to the addition of substrate. In vitro the decrease in activity was accompanied by a decrease in cytochrome P-450 content. This decrease was unaffected by the addition of EDTA to the microsomal suspensions, eliminating the possibility that free radical production was responsible for the decrease in cytochrome P-450. The decrease in activity and cytochrome P-450 content following preincubation of microsomal suspensions with cimetidine could be attenuated if potassium ferricyanide was added to the suspensions. The deethylation activity and cytochrome P-450 content of liver microsomes prepared from cimetidine-treated rats was decreased compared to control animals. The activity and cytochrome P-450 content of microsomes from cimetidine-treated rats could also be restored if microsomes were washed with potassium ferricyanide prior to incubation with substrate. It is proposed that an intermediate complex of cimetidine and cytochrome P-450 could be involved in the inhibition of microsomal metabolism by cimetidine.

Control of gastric acid is accomplished either by buffering it with antacids or by preventing acid secretion with H2-receptor antagonists. Advantages of antacids are their rapid onset of action and the possibility of precisely titrating intragastric pH. In practice, however, they are cumbersome to use because they must be administered frequently (often hourly) and thus require excessive nursing time. In addition, their use often leads to undesirable side effects, such as diarrhea. Cimetidine and ranitidine are H2-receptor antagonists that differ primarily in their potency, ranitidine being four to ten times more potent than cimetidine. With either drug, the patient's intragastric pH falls below 5 by about the fourth hour after the dose. One way to avoid the peaks and valleys of acid secretory control is to use constant infusion. Infusion rates of 50 mg/hr of cimetidine preceded by loading doses of 300 mg of cimetidine often produce a constant intragastric pH above 5. It is essential that intragastric above 5. It is essential that intragastric pH be checked and infusion rates increased or antacids added if pH drops below 5. Bauer used constant infusion of cimetidine in patients with upper gastrointestinal bleeding. He found constant infusion more successful, but his end-point was merely to stabilize the patient before surgery. At UC Davis, we compared constant infusion with intermittent dosing (300 mg of cimetidine every six hours) in patients admitted to the intensive care unit with upper gastrointestinal bleeding.

The oral administration of pirenzepine (PRZ), an antimuscarinic agent, has a variable effect on gastric acid secretion in patients with duodenal ulcer, and it seems to potentiate cimetidine-induced inhibition of secretion. The possibility of a pharmacokinetic interaction between these drugs was examined in eight patients who received cimetidine and PRZ alone and in combination in a crossover fashion. Cimetidine, 600 mg b.i.d., PRZ, 50 mg b.i.d., or combination therapy were each given for 1 week before the study. Serum samples were serially drawn during each dosing interval for determination of cimetidine and PRZ concentrations by HPLC and RIA, respectively. Cimetidine given alone or with PRZ exhibited diurnal variation, as the peak serum concentration was lower after the nighttime dose than after the morning dose. PRZ showed intersubject variation. However, each drug failed to alter the pharmacokinetic indices of the other. The times to attain the peak serum concentration were not significantly different for cimetidine alone or with PRZ, arguing against an effect of PRZ on gastric motility in the doses we used. The greater and prolonged acid inhibition with the combination of cimetidine and PRZ, therefore, may stem from a synergistic action of both drugs on receptor sites on gastric parietal cells.

A blinded, prospective study of the association between cimetidine treatment and altered mental status (MS) was evaluated in 217 surgical intensive care patients stratified by the degree of renal or hepatic dysfunction or both. The cimetidine and noncimetidine groups did not differ in blood chemistries, physiologic-metabolic data, or concurrent medications. There was a correlation between treatment with cimetidine and changes in MS (p less than 0.0001). The MS changes with cimetidine ranged from 33% for neither hepatic nor renal dysfunction to 80% for both renal and liver impairment. The magnitude of MS change was influenced by disease and serum concentration, with patients with both renal and liver disease having the greatest MS change at the highest serum concentrations. The type of MS change was also disease specific. All MS change cleared within 24 to 36 hours of stopping the drug. It appears that both dosage and underlying disease state are important factors determining the nature and severity of cimetidine-associated mental status changes.

Cimetidine, an effective gastric hydrogen receptor antagonist, is evaluated as a secretion eliminator in a routine double contrast upper-gastrointestinal study to improve areae gastricae visualization. One-hundred patients in a double-blind study used cimetidine or a placebo. Results suggest that acid secretion blockage with limited dosage has no advantage in micromucosal visualization.

The effect of 600 mg of cimetidine given twice daily on 24-hour intragastric hydrogen ion (H+) concentration was compared with that of the standard regimen of 300 mg of cimetidine given four times daily in six patients with asymptomatic duodenal ulcer. According to the double-blind, Latin-square, repeated-measures design, all subjects followed each cimetidine regimen and a placebo regimen for one week. Acid secretion studies and determinations of drug and gastrin levels in the blood were carried out on the last day of each treatment week. Although 600 mg of cimetidine BID suppressed H+ after breakfast and during the night, compared with placebo treatment (P less than 0.01), the 300-mg QID regimen suppressed H+ only after breakfast and supper (P less than 0.05). A higher percentage of pH readings greater than or equal to 3.0 were obtained with 600 mg of cimetidine BID than with 300 mg of cimetidine QID during the night (P less than 0.05); compared with percentages when placebo was taken, the percentages of pH readings greater than or equal to 3.0 were greater both overnight and during a 24-hour period only when 600 mg of cimetidine was given BID (P less than 0.01). The observed difference in intragastric H+ suppression after each regimen could not be explained by variations in serum concentrations of cimetidine or serum concentrations of gastrin. Despite similar peaks of serum cimetidine after evening doses of 300 or 600 mg of cimetidine, nocturnal intragastric acidity was lower in subjects given 600 mg BID. Further, H+ levels after lunch were similar in both cimetidine-treated groups, despite markedly higher serum cimetidine concentrations in patients receiving 600 mg BID. Pharmacokinetic studies showed equivalent elimination half-times and 24-hour areas under the curve of serum cimetidine concentration in patients on the two cimetidine regimens. Postprandial integrated gastrin responses were of similar magnitude in patients on either cimetidine regimen. There was no significant difference in mean serum gastrin concentrations during the night in placebo-treated and cimetidine-treated patients. Only a weak correlation was observed between H+ and serum gastrin concentration. Although a fluctuation of the H+:gastrin ratio occurred after each meal in all groups, the ratio was suppressed by both dosages of cimetidine. The findings suggest that a regimen of 600 mg of cimetidine BID is superior to the standard regimen of 300 mg QID in suppressing intragastric acidity in patients with asymptomatic duodenal ulcer.

A single intravenous dose of cimetidine 200mg was administered to 6 patients with severe chronic renal failure one hour prior to haemodialysis. The plasma concentrations of cimetidine and its sulphoxide metabolite at the start of haemodialysis were 2.74 +/- 0.12 and 0.76 +/- 0.08 microgram/ml, and after dialysis for 4h 1.08 +/- 0.10 and 0.51 +/- 0.08 microgram/ml, respectively (mean +/- SE). The average haemodialysis clearance (ClHDa) of cimetidine during dialysis was 46-92 ml/min at a dialysate flow rate of 320 ml/min and blood flow rates in the 6 patients between 160-240 ml/min. The mean ClHDa of the sulphoxide metabolite was 44% higher than that of cimetidine, and ranged between 49-148 ml/min. During haemodialysis the mean plasma elimination half-life (t 1/2) of cimetidine was 3.24h (range 2.08-5.08) and of the sulphoxide metabolite 9.49h (range 4.70-14.39). There was a significant relationship between the elimination rate constant (beta) and ClHDa of the sulphoxide metabolite (p less than 0.01), but no such relationship was found between beta and ClHDa of cimetidine. The mean total amount of cimetidine eliminated during dialysis was 27.3mg (range 17.9-31.8), which was 9.0-15.9% of the given dose. Between 12.2-21.2mg (mean 15.3) of the sulphoxide metabolite was eliminated in the dialysate. Major adjustment of the dose of cimetidine on days of dialysis is not necessary.

To determine the etiology of the decreased efficacy of cimetidine in burned and critically ill surgical patients, we studied the kinetics and dynamics of the drug in eight burned patients at a mean of 12 days after the burn. The kinetics were compared with those of nine healthy controls. The elimination half-life of cimetidine in burned patients was significantly reduced (2.2 v 1.5 hours), and total clearance significantly increased (8.2 v 13.3 mL/min/kg). Creatinine and total cimetidine clearance were highly correlated with size of the burn. In the patients studied, 63% of the dose was excreted in eight hours, compared with 45% after 24 hours in controls. Gastric pH was maintained at 4 or higher as long as plasma levels of cimetidine were held above 0.5 microgram/mL. Thus, the increased clearance of cimetidine might explain the decreased effectiveness of this drug in burned and possibly other surgical patients. Dose schedules may need to be altered to compensate for the enhanced clearance of this drug.

The pharmacokinetics of cimetidine were studied in three newborn infants with reflux esophagitis or stress ulcer. One infant was given 5 mg/kg intravenously (IV), one was given 10 mg/kg IV, and one was given 10 mg orally. Serum concentrations 30 minutes after administration were 1.2 micrograms/ml, 5 micrograms/ml, and 4.2 micrograms/ml, respectively. Concentrations greater than 0.5 micrograms/ml were measured 1, 6, and 9 hours, respectively, after administration. The half-life of the drug ranged from 1.10 to 2.18 hours. These preliminary data suggest that a dose of 5 to 7 mg/kg would effectively suppress gastric acid secretion in neonates.

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)

We studied the effect of cimetidine and theophylline on the metabolism of each drug in 19 elderly patients with stable chronic obstructive pulmonary disease. Each patient received either regular release or sustained release oxtriphylline. Cimetidine was given to some patients in both groups after steady state for theophylline was achieved. Multiple serum theophylline and cimetidine measurements were performed. Cimetidine decreased theophylline clearance by an average of 37.8% (26.2 to 46.7) for regular release and 33.4% (22.2 to 45.0) for sustained release oxtriphylline. The apparent volume of distribution was not changed; however, the half-life for theophylline was increased. As there is a linear relationship between the theophylline clearance before and after the addition of cimetidine and a linear relationship between trough and peak values before and after cimetidine, these 2 relationships may be used to predict clearance values and serum levels after cimetidine treatment when the initial values are known.

The new and convenient method for the separation, isolation and characterization of the N-ciano-N'-methyl-N"-(2-/(5-methylimidazol-4-yl)methylthio/ethyl) guanidine and its biotransformation and degradation products was developed. Mass spectra obtained with the FAB (Fast Atom Bombardment) method are described. This method proved to be very successful for the analysis and characterization of studied compounds.

The pharmacokinetics of cimetidine were evaluated using a linear system analysis that was formulated specifically to resolve the second peak in the blood drug concentration profile after oral dosing. The analysis exemplifies a new approach to pharmacokinetic modeling, which appears to be a valuable alternative to linear compartmental or physiological modeling. The formulation of linear system analysis according to a certain interpretation of a pharmacokinetic phenomenon avoids the complexity of conventional modeling, which often obscures the significance of the kinetic parameters. The new approach should result in a more rational analysis of pharmacokinetic phenomena because the less important pharmacokinetic processes are not specifically modeled but are still accounted for in the mathematical treatment. The bioavailability of cimetidine calculated by deconvolution agrees with previous findings. The model proposed to describe the second peak after oral absorption appears to agree well with the data and the hepatic recycling reported for cimetidine.

In 8 healthy subjects the absorption of cimetidine was investigated when given alone, together with 60 ml aluminium/magnesium hydroxide containing antacid (neutralising capacity 26 mmol HCl/10 ml), and together with liquid metoclopramide 14 mg. The antacid significantly (P less than 0.01) reduced the bioavailability (area under the plasma level-time curve) of cimetidine, on average by one third. Metoclopramide also reduced the bioavailability by an average of 22%. The reductions were associated with significantly reduced excretion of cimetidine in urine. There was no change in the half-life or renal clearance of cimetidine, supporting the hypothesis of reduced gastrointestinal absorption. The results indicate that cimetidine and antacids should not be given together, and that the dose of cimetidine may have to be increased if it is administered concomitantly with metoclopramide.

Metoclopramide was found to increase the absorption rate constant (ka) of cimetidine by the duodenum and jejunum in both ligated and unligated rats. The increase of ka of cimetidine in the ligated rats cannot be interpreted in terms of an increase in the gastric emptying rate, which has been suggested to be the main effect of metoclopramide. The pH values of the stomach, duodenum and jejunum increased following the administration of metoclopramide. Atropine also increased the pH value of the duodenum, but it did not increase the ka of cimetidine. Consequently, the increase of ka of cimetidine, following administration of metoclopramide, was not due to the elevation of intestinal pH. On the other hand, metoclopramide significantly increased the blood flow by about 67.3 and 29.7% at the duodenum and jejunum, respectively, when the intestinal blood flow was measured by the hydrogen clearance method. Atropine had no effect on the intestinal blood flow. Based on these results, it was concluded that the increase of intestinal blood flow may be one of the factors for the increase of ka of cimetidine following the administration of metoclopramide. From the results of multi-line fittings of the plasma concentration data following oral, intraduodenal, intrajejunal and intraileac administrations of cimetidine with metoclopramide treatment, it was suggested that metoclopramide increased the intestinal transit time of subsequently administered drugs, as well as the gastric emptying rate.

Aging and cimetidine may each impair hepatic microsomal drug metabolism. To test if and by what mechanisms advanced age may increase sensitivity to the inhibitory effects of cimetidine, the interaction of these two factors with aminopyrine metabolism in the rat was studied using a correlative approach. Initial studies using the aminopyrine breath test indicated that a 40 mg/kg dose of cimetidine, i.p., impaired the 14CO2 exhaled by up to 76% more in aged (26-month) than in young (3- to 4-month-old) rats. Using an isolated liver perfusion to dissect out hepatic components of this phenomenon, it was found that various doses of cimetidine impaired aminopyrine clearance to a greater degree (P less than 0.05) in aged than in young livers. However, cimetidine metabolism in this system ranged from 36 to 78% less in aged versus young livers (P less than 0.05). Subsequent in vitro studies indicated that microsomes isolated from aged livers also averaged a 76% lower rate of cimetidine metabolism (P less than 0.05). A fixed cimetidine concentration, however, inhibited aminopyrine demethylation to the same degree in aged versus young rats (P less than 0.05). In vivo pharmacokinetics showed an age-related decrease in both aminopyrine and cimetidine systemic clearance. In the young rat the liver contributed about 30% to total systemic clearance of cimetidine. In the aged rat, all clearance was renal. Despite a decrease in glomerular filtration rate, net tubular cimetidine secretion was well-maintained. Despite this, absence of the hepatic component resulted in decreased overall systemic clearance of the drug in aged rats. It is concluded that (1) the aged rat liver exhibits impaired cimetidine metabolism, resulting in decreased overall systemic clearance of the drug despite normal net renal tubular secretion, (2) there is no age-related enhanced sensitivity to cimetidine of the hepatic microsomal oxidizing system using aminopyrine as the probe drug, and (3) the larger inhibition of aminopyrine metabolism in aged rats following various doses of cimetidine is due to decreased overall cimetidine clearance, resulting in higher concentrations of the inhibitor in the liver of aged rats.

1 The pharmacokinetics of cimetidine and its sulphoxide metabolite was studied after a single intravenous dose of 200 mg cimetidine in nine patients with normal renal function and ten patients with severe renal failure on regular haemodialysis and during continuous oral cimetidine treatment in ten patients with normal renal function and 31 patients with different degrees of renal failure. 2 In normal renal function a mean of 47.3% of the single intravenous dose was excreted as unchanged drug and 12.8% as cimetidine sulphoxide. The mean plasma elimination half-life (T1/2) of cimetidine was 2.0 h and of cimetidine sulphoxide 1.7 h. 3 In severe renal failure a mean of 2.2% of the single intravenous dose was excreted as unchanged drug and 0.5% as cimetidine sulphoxide. The mean plasma T1/2 of cimetidine was 3.9 h. The plasma concentrations of the sulphoxide metabolite increased successively with time after dosing and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients g and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients g and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients with different degrees of renal failure given reduced doses of cimetidine the plasma concentrations of the sulphoxide metabolite were higher with decreasing renal function. The mean plasma T1/2 of cimetidine was 3.1 h in mild renal dysfunction (creatinine clearance 50-75 ml/min) and 4.5 h in severe renal failure (creatinine clearance 5-15 ml/min) and of cimetidine sulphoxide 5.3 and 14.4 h respectively. 5 Toxicity studies of cimetidine sulphoxide may be needed to assess if high plasma concentrations of the sulphoxide metabolite in severe renal failure are of clinical significance.

The procedure of deconvolution to evaluate the rate and the extent of input from absorption data and data from intravenous administration is the most fundamental and least assumptive method of accurately evaluating drug absorption in linear pharmacokinetics. It is shown for linear systems that if the absorption response and the response from an intravenous infusion or bolus administration are both well approximated by a polyexponential function, then the rate of absorption can be expressed as a sum of exponentials. An algorithm and computer program are presented whereby the absorption function is uniquely defined from the model-independent parameters of the polyexponential expressions fitted to the absorption data and data from intravenous administration. Fitting a sum of exponentials to data has become a routine procedure in pharmacokinetics. The method presented therefore makes the previously complex task of deconvolution a simple procedure. The deconvolution approach is discussed in relation to conventional methods of evaluating drug absorption and appears to have some distinct advantages over these methods. The method is tested using simulated data and demonstrated using pentobarbital and cimetidine data from human subjects.

Nine healthy normal subjects received verapamil, 10 mg iv, before (control) and during cimetidine dosing (300 mg every 6 hours), and verapamil, 120 mg po, twice in the same manner. After intravenous doses, the t1/2 (means +/- SE: control, 3.60 +/- 0.40 hours; cimetidine trial, 4.30 +/- 0.60 hours), volume of distribution (5.8 +/- 0.6 vs. 6.6 +/- 0.9 L/kg), and total clearance (19.2 +/- 1.5 vs. 18.4 +/- 1.6 ml/min/kg) did not change during cimetidine dosing. After oral doses, the t1/2 (4.25 +/- 0.57 vs. 4.60 +/- 0.70 hours), plasma AUC (585 +/- 113 vs. 506 +/- 82 ng/ml X hr) and absolute bioavailability (35% +/- 7% vs. 30% +/- 5%) did not differ between control and cimetidine trials, respectively. Five of the subjects also received lidocaine, 25 mg iv, once in the control state and once during the cimetidine regimen described above. Lidocaine clearance fell (665 +/- 216 vs. 527 +/- 134 ml/min; P less than 0.05) during cimetidine therapy, resulting in a trend toward a longer t1/2 (1.81 +/- 0.41 vs. 2.44 +/- 0.42 hours; 0.1 greater than P greater than 0.05) with no change in volume of distribution (1.77 +/- 0.66 vs. 1.99 +/- 0.81 L/kg). Verapamil pharmacodynamics (ECG PR interval, blood pressure, and heart rate) were evaluated after intravenous doses. A decrease in mean arterial pressure (8 +/- 1 vs. 9 +/- 2 mm Hg) and a reflex increase in heart rate (14 +/- 3 vs. 17 +/- 2 bpm) were no different in the control and cimetidine trials.(ABSTRACT TRUNCATED AT 250 WORDS)

25 patients with different degrees of chronic stable renal failure received oral treatment with cimetidine over 6 days and a final dose in the morning of day 7. The doses of cimetidine were reduced according to the degree of renal failure. Plasma concentrations of cimetidine were determined before the morning dose on days 2,3,6 and before the final morning dose and during the day on day 7. 24-hour excretions of cimetidine were measured during the study and on day 7, 6 to 9 hours after the final morning dose. There were significant linear relationships between the values of creatinine clearance and plasma elimination rate constant of cimetidine (p less than 0.0025) and between the values of creatinine clearance and renal clearance of cimetidine (p less than 0.05). On the basis of the morning plasma concentrations before and the plasma concentration curve after the final morning dose on day 7 the following dose recommendations according to pretrial values of creatinine clearance are recommended for cimetidine treatment in renal failure: 5 to 15ml/min 200mg 2 or 3 times daily, 15 to 30ml/min 200mg 3 times daily and 30 to 75ml/min 200mg 4 times daily.

Cimetidine and ranitidine interact with microsomes from human and pig liver and with purified cytochrome P-450 in the ligand-type manner. The affinity for cimetidine is about 10 times as high as that for ranitidine. Accordingly amplitudes of the specta are much higher for cimetidine. These results are in accordance with those obtained earlier with rat liver microsomes. The inhibitory potency of either compound with regard to dealkylation of 7-ethoxycoumarin appears to be less in the human preparation.

Cimetidine absorption after a single 300 mg oral dose was evaluated in six normal subjects in the absence or presence of sucralfate. Sucralfate was ingested four times a day for 2 days prior to and for two additional doses on the day of cimetidine ingestion. Sucralfate coadministration had no statistically significant influence on the rate or extent of cimetidine absorption.

Since its introduction some years ago continuous ambulatory peritoneal dialysis (CAPD) has proved to be a valuable alternative to haemodialysis in the treatment of uraemia. Factors contributing to the transport of solutes through the peritoneal membrane are discussed and the literature concerning the pharmacokinetic aspects of CAPD is reviewed.

The development of new methods to study transport processes in renal epithelia has greatly enhanced our knowledge of the mechanisms involved in the transport of a number of endogenous compounds. More recently, these methods have been applied to study mechanisms of specific drug transport. This article is intended to provide an overview of the various methods used to study renal elimination of compounds. References to more detailed reviews of the individual methods are provided. Studies of the renal transport of cimetidine, a histamine H2-receptor antagonist, are presented to illustrate the application of these methods to the study of specific drugs. Methods such as clearance techniques and the Sperber chicken preparation used to study renal elimination of compounds in whole animals are briefly described. Techniques to identify the site of renal transport including stop flow, isolated perfused tubules, and micropuncture methods are discussed and references to more technical reviews are cited. The more recently developed methods of isolated membrane vesicles for studying transport across the individual polar membranes of the proximal tubule are discussed along with the relevant studies of the use of these membranes in elucidating the mechanisms involved in the renal transport of cimetidine. Finally, the use of cultured renal epithelial cell lines in studying renal transport is described. Knowledge of drug transport mechanisms in the kidney is important both in drug targeting to the kidney and in understanding the pharmacokinetics of renally eliminated drugs. As exemplified by the studies with cimetidine, only by combining the data from experiments using diverse methodology can the mechanisms involved in the renal excretion of compounds be delineated.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanism of the pressor response to metiamide was examined in anesthetized cats. Intravenous administration of metiamide had no effect on blood pressure. Infusion into the lateral ventricle (10 mg/kg/min for 10 min), caused a marked pressor response which was due to an increase in sympathetic outflow since pretreatment of cats with guanethidine completely prevented it. In a rat brain synaptosome preparation, both metiamide and cimetidine displaced [3H] CABA. These data strongly suggest that metiamide increases blood pressure in the cat through a central mechanism involving GABA-receptor antagonism.

Cimetidine pharmacokinetics were studied in 13 otherwise healthy but obese volunteers, having a mean body weight of 113 kg and a mean percentage ideal body weight (IBW) of 179%. Sixteen healthy volunteers of normal body habitus (64 kg, 99% IBW) served as controls. All subjects had normal renal function and no laboratory or clinical evidence of hepatic or cardiac dysfunction. After administration of 200-300 mg of cimetidine by rapid intravenous injection, multiple plasma samples obtained over the next 24 h were analyzed for cimetidine concentration by high pressure liquid chromatography. Elimination half-life was not different between obese and control subjects (2.23 versus 2.08 h). Apparent volume of distribution was also similar between subject groups (120 versus 106), as was total metabolic clearance (616 versus 579 ml/min). Using percentage IBW as a measure of obesity, no relationship was found between percentage IBW and apparent volume of distribution (r = 0.29). Cimetidine similarly distributes into IBW in both obese and normal weight subjects, and there is minimal distribution of cimetidine into excess body weight over IBW. Furthermore, there is no difference in total metabolic clearance or half-life of cimetidine between obese and control subjects. Cimetidine dosage in clinical practice should therefore be calculated on the basis of IBW, which better reflects lean body mass, instead of total body weight, which reflects adipose tissue weight in addition to lean body mass.