Roland Gugler

Drug Interactions with Cimetidine

SummaryBecause of widespread (and often uncritical) use of Cimetidine, there is considerable potential for interactions to occur with other drugs.In studies on absorption, benzylpenicillin absorption was not disturbed by Cimetidine in most cases, but a several-fold increase in urinary excretion occurred repeatedly in I subject, indicating that increased absorption of acid-labile compounds may occur in some patients. The absorption of ketoconazole was reduced by more than half with Cimetidine, a consequence of its poor water solubility which is enhanced in acid solution. Conflicting results are reported with tetracycline, the overall absorption of which does not appear to be significantly altered by Cimetidine. Aspirin absorption was halved by Cimetidine in 3 of 6 subjects, when the intragastric pH was raised above 3.5. Cimetidine did not affect the absorption of ampicillin, co-trimoxazole or prednisolone.Cimetidine has been shown to inhibit various microsomal drug-metabolising enzymes in animal as well as human liver, most likely through the binding of the imidazole ring structure of Cimetidine to the haeme moiety of cytochrome P-450. In 7 studies, Cimetidine uniformly prolonged antipyrine half-life by 18 to 37% and reduced its clearance by 10 to 27%. After chronic dosing with Cimetidine, warfarin clearance was reduced from 3.4 to 2.5ml/min, whilst the volume of distribution and elimination half-life remained unchanged. Steady-state warfarin concentrations, as well as Prothrombin times, increased upon addition of Cimetidine to the treatment regimen. Warfarin concentration and effect both returned to pre-Cimetidine values when Cimetidine was withdrawn. Amongst the benzodiazepines, diazepam, desmethyldiazepam and chlordiazepoxide plasma clearance values were reduced by Cimetidine by 43, 28 and 63 %, respectively, and half-lives increased accordingly, while volumes of distribution and protein binding were not affected. Long term treatment with Cimetidine and diazepam resulted in a 30 to 80% increase in steady-state diazepam concentrations. In contrast, the pharmacokinetics of oxazepam and lorazepam, which are eliminated almost entirely by glucuronidation and not oxidation, were not altered by Cimetidine. Cimetidine also inhibits the metabolism of phenytoin, theophylline and carbamazepine.A single dose of Cimetidine decreased indocyanine green clearance by 23%, which was interpreted as a reduction in hepatic blood flow. The area below the Propranolol concentration-time curve (oral administration) was increased by between 25 and 60 % with Cimetidine and by 25 % after intravenous administration of Propranolol, with no change in elimination half-life, volume of distribution or bioavailability. With chronic oral Propranolol dosing, Cimetidine increased the steady-state concentration from 23.2 to 44.9ng/ml. The bioavailability of labetalol almost doubled from 30 to 54 % with Cimetidine, with no change in half-life and systemic clearance. The oral clearance and elimination half-life of chlormethiazole was increased by 30 and 50%, respectively, by Cimetidine. Studies with high hepatic clearance drugs have not consistently shown cimetidine-induced changes in systemic clearance (liver blood flow dependent), but oral clearance increased in all cases, consistent with inhibition of drug metabolism.Peculiarities of Cimetidine effect on drug metabolism are (a) only about 20% of a Cimetidine dose is metabolised in man, as compared with a much larger fraction with other inhibitory drugs; (b) the maximum effect attained occurs within I day whereas offset of effect varies with individual interacting drugs; (c) the degree of inhibition of metabolism is much more pronounced in patients with already impaired liver function (i.e. liver disease).Antacids of a weak neutralising capacity (10 to 15mmol/dose) did not influence the absorption of Cimetidine. However, antacids (aluminium plus magnesium hydroxide) with a neutralising capacity between 26 and 41 mmol/10ml reduced the bioavailability of Cimetidine by 20 to 35%. A recent study with an aluminium plus magnesium hydroxide antacid of 70mmol/10ml did not affect Cimetidine bioavailability. The antacid preparation used differed from others by a disproportionate increase in the aluminium hydroxide content. Metoclopramide and propantheline also reduced the absorption of Cimetidine by an average of 20 %, indicating the importance of gastric emptying for Cimetidine absorption. Phenobarbitone administration over 3 weeks led to an increase in Cimetidine plasma clearance by 18%, mainly due to an increase in the non-renal clearance, but probably also partially due to a reduction in Cimetidine absorption.The most important clinical consequences of interactions with Cimetidine primarily involve inhibition of drug metabolism. Clinically important interactions are predominantly manifested in those drugs which have a narrow therapeutic index (e.g. Phenytoin, warfarin, theophylline). The interaction leads to higher steady-state blood concentrations and hence increases the incidence of side effects and toxicity. Adverse effects of such interactions can be avoided by careful monitoring and adjustment of dosage for those drugs which undergo phase I metabolic detoxification in the liver when it is necessary to administer such drugs concomitantly with Cimetidine.

Clinical Pharmacokinetics of Cimetidine

SummaryCimetidine 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 (Vdβ 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 μg/ml (range 0.64–1.64 μg/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. Metabolites of cimetidine in man represent 25 to 40% of the total elimination, with 1 major metabolite (cimetidine sulphoxide; 10–15%) and 1 minor metabolite (hydroxymethyl cimetidine; 4%). Elimination of cimetidine is accelerated by an average of 15% in the presence of phenobarbitone, due to induction of its metabolism.The clearance of cimetidine is increased in children, due to increased renal elimination mechanisms. With increasing age, the volume of distribution of cimetidine decreases, total plasma clearance decreases as a function of decreasing renal clearance, plasma half-life increases, and the duration of effective plasma concentrations (above 0.5 μg/ml) increases as well.In patients with advanced renal insufficiency, total plasma clearance is reduced from a mean of 500 ml/min to less than 200 ml/min, mainly due to a decrease in renal clearance to 50 ml/min or less. Elimination half-life increases from 2 to 4–5 hours in renal failure patients. The absolute bioavailability in renal failure patients is unchanged or slightly higher compared with controls. A dose reduction for cimetidine is suggested according to the degree of renal impairment, with 400mg daily being recommended in patients with minimal renal function. Cimetidine is dialysable during haemodialysis, but less than 20% of the dose is removed after a single dose, and dose adjustment is seldom necessary.In patients with severe liver cirrhosis, the non-renal clearance of cimetidine is significantly reduced, but bioavailability as well as the duration of effective plasma concentrations (above 0.5 μg/ml) is increased. A dramatic reduction of total plasma clearance and a prolongation of half-life up to 10 times normal may occur when renal failure is associated with chronic liver disease. In intensive care patients, the dosage of cimetidine frequently has to be increased to 1800mg daily to achieve sufficient elevation of gastric pH, and plasma concentrations above 1.5 μg/ml are required in most patients. The mean elimination half-life in these patients is 2.7 hours, but a wide variation in all parameters is observed.Cimetidine crosses the placenta and is detectable in the fetus in considerable concentrations. It also is secreted into breast milk of nursing mothers and may reach the infant in amounts of several milligrams daily.Cimetidine concentrations between 0.5 and 1.0 μg/ml are required to suppress gastric acid secretion under basal conditions or stimulated by pentagastrin or food. Attempts to correlate plasma concentrations of cimetidine or any of the pharmacodynamic parameters to duodenal ulcer healing have so far failed, and thus prediction of therapeutic response from pharmacokinetic data appears disappointing. In cases of overdosage with cimetidine, the pharmacokinetics are unchanged, even with plasma concentrations above 30 μg/ml. Central nervous system side effects such as mental confusion develop in elderly patients and in patients with severe renal or hepatic impairment. In such cases concentrations of cimetidine in the CSF are elevated due to high plasma concentrations and due to a more permeable blood/brain barrier in patients with liver disease.

Disposition of valproic acid in man.

SummaryThe pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9±2.6 h in the single dose and 17.3±3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064±0.0011 l/kg×h. The apparent volume of distribution was small at 0.15±0.2 l/kg. The mean steady state plasma concentration (Css) reached after 4 days was 81.3±13.0 µg/ml. Css observed was lower than Css predicted (99.2±14.7 µg/ml) from single dose kinetics (p<0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7±0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.

Effects of Antacids on the Clinical Pharmacokinetics of Drugs: An Update

SummarySince a previous review by Hurwitz was published in 1977 a large number of reports on drug interactions with antacids have appeared, few of which are of clinical relevance.Tetracyclines form insoluble complex molecules by metal ion chelation with various antacids; tetracycline absorption may be decreased by more than 90% by this interaction. Of the new class of quinolone antibiotics, the absorption of Ciprofloxacine and ofloxacine is reduced by 50 to 90% in the presence of aluminium- and magnesium hydroxide-containing antacids.In contrast to early work showing inhibition of the absorption of β-adrenergic blocking drugs by antacids, subsequent studies did not confirm a reduction in the bioavailability of either atenolol or propranolol during antacid treatment; indeed, they showed an increase in the plasma concentrations of metoprolol when the drug was coadministered with an antacid. The bioavailability of Captopril was significantly reduced in the presence of an antacid, and lower plasma concentrations of this angiotensin-converting enzyme inhibitor were accompanied by a reduction of its effect on the systolic blood pressure of the patients. The absorption of the cardiac glycosides digoxin and digitoxin is not inhibited by antacids to a significant degree, although earlier studies had shown a positive effect when the dissolution of the glycoside preparations was relatively poor.Antacids reduce the bioavailability of the H2-receptor antagonists Cimetidine and ranitidine only when high antacid doses are used and when the drugs are administered simultaneously. The bioavailability of famotidine was not significantly altered by a potent antacid preparation, although a trend towards reduced absorption was observed. Iron absorption is significantly decreased in the presence of sodium bicarbonate and calcium carbonate, but is nearly complete when coadministered with aluminium-magnesium hydroxide.Nonsteroidal anti-inflammatory drugs such as naproxen, tenoxicam, ketoprofen, ibuprofen and piroxicam are not affected in their absorption by antacid treatment. Theophylline bioavailability is unchanged when the drug is given together with antacids, although its rate of absorption may be altered, leading to a reduction or an increase in the time of the occurrence of peak plasma drug concentrations.

Pharmacokinetics and Bioavailability of Cimetidine in Gastric and Duodenal Ulcer Patients

SummaryThe pharmacokinetics and bioavailability of cimetidine after 200mg 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 495ml/min was mainly due to renal clearance (293ml/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 0.5μg/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.

Impaired Cimetidine Absorption Due to Antacids and Metoclopramide

SummaryIn 8 healthy subjects the absorption of cimetidine was investigated when given alone, together with 60 ml aluminium/magnesium hyroxyde containing antacid (neutralising capacity 26 mmol HCl/10 ml), and together with liquid metoclopramide 14 mg. The antacid significantly (P<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.

Clofibrate disposition in renal failure and acute and chronic liver disease.

SummaryThe 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.

Cimetidine plasma concentration‐response relationships

Cimetidine plasma concentration‐response relationships were investigated in six healthy subjects using suppression of gastric acid secretion under continuous pentagastrin stimulation (1.5 µg/kg/hr) as a test model. With the Hill equation the sigmoid was preferable to the linear relationship between plasma concentration and effect, and there were significant correlations with p values under 0.01 in all but one subject. From the individual curves a mean plasma level of 0.78 µg/ml (range 0.54 to 1.04 µg/ml) for 50% inhibition of gastric acid secretion was determined; mean concentration for 90% inhibition was calculated to be 3.9 µg/ml. The model described should allow determination of whether different patient populations (e.g., healthy subjects, patients with ulcers, male and female patients, patients with renal or liver disease) differ from one another in concentration‐response relationships to histamine H2‐receptor antagonists, so that appropriate drug plasma levels should be achieved for specific degrees of inhibition of gastric acid secretion.

Single‐ and multiple‐dose metronidazole kinetics

Kinetics of metronidazole and its metabolites were examined after single oral and intravenous doses and multiple oral doses in seven subjects by a sensitive HPLC assay. After 400 mg metronidazole IV, mean Vdβ was 1.05 l/kg. Mean plasma t½ was 8.3 hr with a ClTBC of 1.31 ml/min/kg. Clearance to the major metabolites, 2‐hydroxy‐metronidazole and 1‐acetic acid metronidazole, accounted for over 90% of the ClTBC. After a single oral 400‐mg metronidazole dose, the development of peak metronidazole plasma concentrations of 6.9 μg/ml averaged 2.3 hr after dosing. Systemic oral bioavailability was complete (98.9%). During twice‐daily multiple metronidazole dosing, 400 mg, metronidazole kinetics were the same. Elimination t½ was 8.3 hr and average predicted steady‐state metronidazole concentrations during one dosing interval (6.3 ± 0.5 μg/ml; mean ± SE) were equal to the observed concentrations (6.9 ± 1 μg/ml). Urinary excretion of unchanged metronidazole was below 10% of the total dose. Seventy‐five percent of the dose was 2‐hydroxy‐metronidazole and 1‐acetic acid metronidazole, and 15% was conjugates of metronidazole and 2‐hydroxy‐metronidazole.

The effect of pindolol on exercise-induced cardiac acceleration in relation to plasma levels in man.

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.