The effect of cimetidine and ranitidine on paracetamol glucuronidation and sulphation in cultured rat hepatocytes

Emery, Sean; Oldham, Harriet G.; Norman, S.J.; Chenery, Richard J.

doi:10.1016/0006-2952(85)90678-1

Cited by 20 publications

(10 citation statements)

References 14 publications

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“…In human liver microsomes, azithromycin has been shown to inhibit cytochrome P-450 IIIA4, although to a lesser extent than erythromycin does (11). UDP glucuronyltransferases, the microsomal enzymes implicated in the hepatic glucuronidation of ZVD (14), can be induced and inhibited by various drugs (8,10,25,27,29). Since ZVD has a rather low therapeutic margin, any alteration of its metabolism could lead to toxicity or could prevent its effect.…”

Section: Resultsmentioning

confidence: 99%

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition

Chave

Munafo

Chatton

et al. 1992

Antimicrob Agents Chemother

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Toxoplasmic encephalitis is one of the leading causes of morbidity in patients with AIDS. Lifelong treatment is needed to prevent relapses, and primary prevention is desirable in high-risk patients, but the available drugs are often poorly tolerated. Azithromycin (AZM) has been considered a drug candidate because of its efficacy in the animal model and its kinetic properties, which would allow intermittent administration. The tolerability and kinetics of AZM and its effect on the disposition of zidovudine (ZVD) were therefore evaluated in a preliminary open study in nine human immunodeficiency virus-infected patients. AZM was administered once weekly for 5 weeks 2 h before the usual morning ZVD dose. The day before and on the first and fifth AZM dosings, blood samples were drawn every 30 min during 5 h for determination of the concentrations of ZVD and its glucuronide metabolite. Blood samples were drawn for AZM measurement over 72 and 360 h on the first and fifth AZM administrations, respectively, as well as before and 3 h after dosing on the second, third, and fourth AZM dosings. After the first and fifth administrations, maximum AZM concentrations in serum were 0.6 + 0.1 and 0.8 ± 0.2 ,uM (mean + standard error of the mean), respectively; times to peak concentration in serum were 3.7 ± 0.2 and 2.9 + 0.4 h, respectively; areas under the plasma concentration-time curves were 9.2 ± 1.6 and 9.3 + 2.0 ,ug h/ml, respectively; and half-lives were 61.0 + 5.4 and 63.8 ± 6.7 h, respectively.On days -1, 1, and 29, ZVD kinetic parameters were as follows: maximum concentrations in serum, 3.1 + 0.6, 4.3 + 0.6, and 4.2 + 0.9 ,uM, respectively; times to maximum concentration in serum, 1.1 + 0.4, 0.8 ± 0.2, and 1.2 ± 0.3 h, respectively; areas under the plasma concentration-time curves, 5.3 + 0.9, 5.9 + 0.6, and 5.7 + 0.8 ,ig. h/ml, respectively; and half-lives, 1.3 + 0.08, 1.4 ± 0.04, and 1.3 + 0.04 h, respectively. Except for transient mild abdominal cramps that occurred at 2 to 3 h postdose (6 of 45 exposures) and nausea (4 of 45 exposures), neither subjective nor objective side effects were observed. The kinetics of AZM were similar after the first and repeated administrations, and the disposition of ZVD was not altered by this treatment. The efficacy of AZM in preventing cerebral toxoplasmosis can therefore be safely tested in human immunodeficiency virus-infected patients concomitantly treated with zidovudine.

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Section: Resultsmentioning

confidence: 99%

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition

Chave

Munafo

Chatton

et al. 1992

Antimicrob Agents Chemother

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“…DCPQ likely caused increased exposure of the radiotracer to metabolizing enzymes in liver. By contrast, cimetidine may have protected [ 11 C]rhodamine-123 from metabolism, possibly through its known ability to inhibit P450-mediated pathways [37,38] and/or glucuronidation [39]. …”

Section: Resultsmentioning

confidence: 99%

[11C]Rhodamine-123: Synthesis and biodistribution in rodents

Bao

Liow

et al. 2012

Nuclear Medicine and Biology

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Introduction Rhodamine-123 is a known substrate for the efflux transporter, P-glycoprotein (P-gp). We wished to assess whether rhodamine-123 might serve as a useful substrate for developing probes for imaging efflux transporters in vivo with positron emission tomography (PET). For this purpose, we aimed to label rhodamine-123 with carbon-11 (t1/2 = 20.4 min) and to study its biodistribution in rodents. Methods [11C]Rhodamine-123 was prepared by treating rhodamine-110 (desmethyl-rhodamine-123), with [11C]methyl iodide. The biodistribution of this radiotracer was studied with PET in wild-type mice and rats, in efflux transporter knockout mice, in wild-type rats pretreated with DCPQ (an inhibitor of P-gp) or with cimetidine (an inhibitor of organic cation transporters; OCT), and in P-gp knockout mice pretreated with cimetidine. Unchanged radiotracer in forebrain, plasma and peripheral tissues was also measured ex vivo at 30 min after radiotracer administration to wild-type and efflux transporter knockout rodents. Results [11C]Rhodamine-123 was obtained in 4.4% decay-corrected radiochemical yield from cyclotron-produced [11C]carbon dioxide. After intravenous administration of [11C]rhodamine-123 to wild-type rodents, PET and ex vivo measurements showed radioactivity uptake was very low in brain, but relatively high in some other organs such as heart, and especially liver and kidney. Inhibition of P-gp increased uptake in brain, heart, kidney and liver, but only by up to twofold. Secretion of radioactivity from kidney was markedly reduced by OCT knockout or pretreatment with cimetidine. Conclusions [11C]Rhodamine-123 was unpromising as a PET probe for P-gp function and appears to be a strong substrate of OCT in kidney. Cimetidine appears effective for blocking OCT in kidney in vivo.

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“…We have previously con® rmed that coadministration of ranitidine signi® cantly reduces concentrations of paracetamol glucuronide and increases concentrations of paracetamol in human plasma (Itoh et al 2000). Emery et al (1985) investigated the eOE ects of ranitidine on paracetamol metabolism. Inhibition of paracetamol glucuronyltransferase activity by ranitidine reduced paracetamol conjugation.…”

Section: Discussionmentioning

confidence: 99%

Effect of nizatidine on paracetamol and its metabolites in human plasma

Nagano

Takeyama

2002

Journal of Pharmacy and Pharmacology

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The effect of the histamine H2-receptor antagonist, nizatidine, on plasma concentrations of paracetamol has been investigated with respectto hepatic metabolism. Paracetamol (1000 mg) together with 300 or 150 mg nizatidine or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after administration. Plasma paracetamol and paracetamol conjugates (glucuronide and sulfate) were measured by high-performance liquid chromatography. The pharmacokinetic parameters were calculated from the plasma paracetamol concentration-time curves of each volunteer. The plasma nizatidine concentration was highest (2420.0+/-192.4 and 996.0+/-54.6 ng mL(-1)) in the sample taken 1 h after administration of 300 mg nizatidine (high dose) and 150mg nizatidine (low dose), respectively. Plasma paracetamol concentrations with nizatidine (high and low doses) were increased significantly at 45-120 min and 45-60 min, respectively, compared with placebo. The total area under the plasma paracetamol concentration-time curve from 0 to 180 min (2361.5+/-146.4 and 2085.75+/-73.5 microg min mL(-1)) significantly increased after coadministration of nizatidine (high and low doses), respectively (P < 0.01 vs placebo). Paracetamol glucuronide concentrations with nizatidine (high and low doses) were decreased significantly at 30-45 min and 30 min, respectively, compared with placebo. However, plasma paracetamol sulfate concentrations with nizatidine (high and low doses) were not significantly altered. The coadministration of nizatidine (150 and 300 mg) dose-dependently reduces plasma paracetamol glucuronide concentrations and increases plasma paracetamol concentrations. The effects of nizatidine could result from the inhibition of glucuronyltransferase. Thus, care is necessary when paracetamol and nizatidine are coadministered.

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The effect of cimetidine and ranitidine on paracetamol glucuronidation and sulphation in cultured rat hepatocytes

Cited by 20 publications

References 14 publications

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition

[11C]Rhodamine-123: Synthesis and biodistribution in rodents

Effect of nizatidine on paracetamol and its metabolites in human plasma

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