Reduced steady-state plasma concentrations of chlorpromazine and indomethacin in patients receiving cimetidine

Howes, Christine A.; Pullar, T; Sourindhrin, I.; Mistra, P C; Capel, H; Lawson, Dan; Tilstone, W. J.

doi:10.1007/bf00613934

Cited by 40 publications

(10 citation statements)

References 16 publications

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“…In a study conducted in 10 patients with rheumatoid arthritis receiving indomethacin 100 to 200mg daily (Howes et al 1983), the addition of cimetidine 1.2 g/day for 14 days decreased the steady-state plasma indomethacin concentration (based on 4 data points) from 1.64 ± 0.38 to 1.34 ± 0.35 mg/L (p = 0.02). In addition, the urinary excretion of indomethacin and some of its metabolites decreased from 2.34 ± 3.5 to 1.73 ± 2.11 mg/L per micromole of creatinine (p < 0.05), although these metabolites represent only a small proportion of the urinary metabolic recovery (20%).…”

Section: Indomethacinmentioning

confidence: 94%

“…Long term coadministration of cimetidine resulted in a 35% decrease in the steady-state plasma concentration of chlorpromazine in 8 patients who had received chlorpromazine 75 to 450mg per day for periods ranging from 3 months to 14 years (Howes et al 1983). As the 24-hour urinary ratio of hydroxy-to non-hydroxyphenothiazines fell from 2.54 to 1.74 after cimetidine, the investigators concluded that the reduced plasma concentrations reflected a decrease in chlorpromazine absorption which masked the expected increase in concentrations due to inhibition of chlorpromazine hydroxylation.…”

Section: Chlorpromazinementioning

confidence: 97%

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Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

185

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The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Indomethacinmentioning

confidence: 94%

Section: Chlorpromazinementioning

confidence: 97%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

185

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“…Plasma concentrations of antipsychotic drugs may be influenced by lithium (Rivera-Calimlim et al 1978), phenobarbitone, phenytoin (Linnoila et al 1980), cimetidine (Howes et al 1983) and, as mentioned by Cooper (1978), by several tricyclic antidepressants.…”

Section: Anti-parkinsonian and Other Drugsmentioning

confidence: 96%

Plasma Level Monitoring of Antipsychotic Drugs Clinical Utility

Dahl

1986

Clinical Pharmacokinetics

145

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The steady-state plasma concentrations of antipsychotic drugs show large interpatient variations but remain relatively stable from day to day in each individual patient. Monitoring of antipsychotic drug concentrations in plasma might be of value provided the patients are treated with only 1 antipsychotic drug. Some studies have reported a relationship between therapeutic response and serum antipsychotic drug 'concentrations' as measured using the radioreceptor assay (RRA) method, which measures dopamine receptor-blocking activity in plasma. Most studies, however, have failed to demonstrate such a relationship, and the RRA does not seem to provide the generally useful tool for plasma concentration monitoring of antipsychotic drugs that was hoped for initially. A lack of correlation between dopamine receptor-blocking activity in plasma and therapeutic response may be due to differences in the blood-brain distribution of both antipsychotic drugs and their active metabolites. Chemical assay methods (e.g. GLC and HPLC) have been used in studies which examined the relationships between therapeutic response and antipsychotic drug concentrations in red blood cells and in plasma. It seems that for these drugs, measuring red blood cell concentrations does not offer any significant advantage over measuring plasma concentrations. Reasonably controlled studies of plasma concentration-response relationships using randomly allocated, fixed dosages of chlorpromazine, fluphenazine, haloperidol, perphenazine, sulpiride, thioridazine and thiothixene have been published but often involve relatively few patients. A correlation between therapeutic response and plasma concentrations of thioridazine and its metabolites has not been demonstrated, and plasma level monitoring of thioridazine and its metabolites therefore appears to have no clinical value. Clinical behavioural deterioration concomitant with high plasma concentrations of chlorpromazine and haloperidol have been reported. A dosage reduction might be considered after 2 to 4 weeks' treatment in non-responders who have plasma chlorpromazine concentrations above 100 to 150 micrograms/L or plasma haloperidol concentrations above 20 to 30 micrograms/L. Non-responders and good responders to chlorpromazine treatment, however, have plasma drug concentrations in the same range, and a therapeutic range of plasma chlorpromazine levels has not been defined. Therapeutic plasma haloperidol concentrations (i.e. 'window') in the range of 5 to 20 micrograms/L have been reported by some investigators, but others have found no such relationship.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Indomethacin and these metabolites are excreted in the urine (Duggan et al, 1972;Flower et al, 1985). Allopurinol, a drug which inhibits mixed function oxidase enzymes (Vesell et al, 1970) is often used along with indomethacin and might be expected to inhibit the hepatic microsomal metabolism of indomethacin as has been shown with cimetidine, another inhibitor of this enzyme system (Howes et al, 1983 (Klotz & Reimann, 1980;Fee et al, 1987). The duration of any potential effect of allopurinol on indomethacin metabolism was unknown and therefore, to avoid a prolonged wash-out period, the order of administration was not randomised.…”

Section: Introductionmentioning

confidence: 99%

The effect of allopurinol on the steady‐state pharmacokinetics of indomethacin.

Pullar

Myall

Haigh

et al. 1988

Brit J Clinical Pharma

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The effect of 5 days treatment with allopurinol (300mg) on the pharmacokinetics of indomethacin at steady-state was investigated in eight patients. Allopurinol produced no significant effect on the indomethacin serum concentration-time curve. Allopurinol did not alter significantly the amounts of indomethacin excreted in the urine within 8 h. However, the urinary ratio of N-deschlorobenzoylindomethacin to indomethacin was reduced significantly by allopurinol administration (P < 0.05).

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Reduced steady-state plasma concentrations of chlorpromazine and indomethacin in patients receiving cimetidine

Cited by 40 publications

References 16 publications

Pharmacokinetic Interactions of Cimetidine 1987

Pharmacokinetic Interactions of Cimetidine 1987

Plasma Level Monitoring of Antipsychotic Drugs Clinical Utility

The effect of allopurinol on the steady‐state pharmacokinetics of indomethacin.

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