Metoclopramide kinetics in patients with impaired renal function and clearance by hemodialysis

Lehmann, Craig R.; Heironimus, James D.; Collins, Cleve B.; O'Neil, T J; Pierson, Wayne P.; Crowe, James T.; Melikian, Armen P.; Wright, George J.

doi:10.1038/clpt.1985.41

Cited by 41 publications

(17 citation statements)

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“…For instance, the metabolism of zidovudine and metoclopramide, which is primarily mediated by glucuronidation, is reduced in patients with renal failure. 20,31,32 Acetylation also seems to be reduced in patients with CRF; several reports have demonstrated that the metabolic clearance of procainamide is reduced by approximately 60% in renal failure. 2,23,24 Moreover, a decrease in the acetylation of isoniazid has been reported in patients with CRF.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure

Simard¹,

Naud²,

Jl³

et al. 2008

Journal of the American Society of Nephrology

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Drug metabolism can be affected by chronic renal failure (CRF). Although it is known that several drugs that are known to be acetylated accumulate in CRF, the effect of CRF on N-acetyltransferase (NAT), the enzyme responsible for this acetylation, is unknown. Herein is reported that protein and gene expression of both Nat isoforms in the liver was reduced by Ͼ30% and Nat2 activity was reduced by 50% in rats with CRF compared with control rats. Incubation of hepatocytes with serum from rats with CRF suggested that a circulating factor is responsible for the decrease in protein and gene expression. For testing the hypothesis that parathyroid hormone may be this factor, CRF was induced in parathyroidectomized rats; downregulation of Nat expression and activity was not observed in these rats. Furthermore, addition of parathyroid hormone to cultured hepatocytes induced a decrease in Nat2 protein and gene expression. In conclusion, liver acetylation of drugs in a rat model of CRF is reduced by a downregulation of Nat1 and Nat2 isoforms, secondary to decreased gene expression. Parathyroid hormone seems to be an important mediator of this phenomenon.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure

Simard¹,

Naud²,

Jl³

et al. 2008

Journal of the American Society of Nephrology

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“…Sulfisoxazole is acetylated, glucuronidated, and metabolized partially by CYP2C9. A summary of clinical data showing significant alterations in nonrenal clearance in CRF for a number of drugs is shown in (Table 2) [7,[51][52][53][54][55][56][57][58][59][60][61]. The majority of these studies involve ESRD patients.…”

Section: Clinical Investigations: Effect Of Chronic Renal Failure On mentioning

confidence: 99%

The effect of chronic renal failure on drug metabolism and transport

Dreisbach

Lertora

2008

Expert Opinion on Drug Metabolism & Toxicology

210

154

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Background-Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine.Objectives-The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport.Methods-The National Library of Medicine PubMed was utilized with the search terms 'chronic renal failure, cytochrome P450, liver metabolism, efflux drug transport and uptake transport' including relevant articles back to 1969.Results-Animal studies in CRF have shown a major downregulation (40-85%) of hepatic and intestinal cytochrome P450 (CYP) metabolism. High levels of parathyroid hormone, cytokines, and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein (Pgp) and organic anion transporting polypeptide (OATP) are also affected.Conclusion-CRF alters intestinal, renal, and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.

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“…This would be expected from the large volume of distribution of this drug. Therefore, our results and those of Lehmann et al (1985) suggest that dosage supplementation subsequent to dialysis is unnecessary.…”

Section: Discussionmentioning

confidence: 80%

“…Although previous investigators (Bateman et al, 1981;Lehmann et al, 1985) have examined the basic pharmacokinetics and removal of drug by haemodialysis, the present investigations focussed on a somewhat different aspect of metoclopramide pharmacokinetics in renal failure. When a patient is haemodialysed, the blood is 'cleansed' of end-products of metabolism many of which could be potential inhibitors of drug metabolism (Terao & Shen, 1985).…”

Section: Discussionmentioning

confidence: 99%

Effect of haemodialysis on metoclopramide kinetics in patients with severe renal failure.

Wright

Axelson

Rurak

et al. 1988

Brit J Clinical Pharma

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The kinetics of metoclopramide and the effects of haemodialysis on metoclopramide kinetics were examined in eight uraemic subjects 1 h and 24 h prior to the onset of dialysis. In spite of the relatively minor contribution of renal clearance to total body clearance in normals, metoclopramide kinetics were substantially altered in uraemia. The total body clearance was decreased by 2-4 fold, terminal elimination half-life proportionately increased, while the volume of distribution appeared to be unaffected compared with that previously demonstrated in normal healthy subjects. Haemodialysis does not appear to be effective in removing metoclopramide from the body and metoclopramide clearance subsequent to dialysis is unaltered. The kinetic parameters in the uraemic subjects are not significantly different between drug administrations 1 or 24 h prior to the time of onset of haemodialysis. Following kidney transplantation, in one subject, there appeared to be a rapid return to apparently normal kinetics from the uraemic state.

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Metoclopramide kinetics in patients with impaired renal function and clearance by hemodialysis

Cited by 41 publications

References 0 publications

Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure

Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure

The effect of chronic renal failure on drug metabolism and transport

Effect of haemodialysis on metoclopramide kinetics in patients with severe renal failure.

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