Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies

Kamaluddin, Muhammad Totong; McNally, Paul; Breatnach, Fin; Webb, David; Odell, Edward; Scanlon, Paul D.; Butler, K; O’Meara, A.; O'Marcaigh, Aengus

doi:10.1080/080352501317061675

Cited by 28 publications

(36 citation statements)

References 11 publications

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“…This result is in agreement with clinical reports of drug-drug interactions upon coadminis- tration of vincristine with CYP3A inhibitors such as itraconazole and nifedipine (Fedeli et al, 1989;Bohme et al, 1995;Kamaluddin et al, 2001;Sathiapalan and El-Solh, 2001). The metabolism of vincristine primarily by CYP3A is also consistent with the physicochemical features of vincristine; in this case, a large molecular volume.…”

Section: Discussionsupporting

confidence: 91%

“…The metabolism of structurally related compounds, vinblastine and vindesine, with human liver microsomes was inhibited by vincristine and other CYP3A-selective inhibitors, which suggests that CYP3A participates in the metabolism of vincristine Zhou-Pan et al, 1993). In addition, numerous clinical drug-drug interactions with itraconazole and nifedipine have been reported for vincristine, and the observed increases in neurotoxicity are consistent with the CYP3A-mediated metabolism of vincristine (Fedeli et al, 1989;Bohme et al, 1995;Kamaluddin et al, 2001;Sathiapalan and El-Solh, 2001). The genetically polymorphic expression of the CYP3A5 enzyme may contribute to the clinically observed interindividual and interracial variability in vincristine response.…”

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confidence: 52%

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Selective Metabolism of Vincristine in Vitro by Cyp3a5

Dennison¹,

Kulanthaivel²,

Barbuch³

et al. 2006

Drug Metab Dispos

152

117

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ABSTRACT:Clinical outcomes of vincristine therapy, both neurotoxicity and efficacy, are unpredictable, and the reported pharmacokinetics of vincristine have considerable interindividual variability. In vitro and in vivo data support a dominant role for CYP3A enzymes in the elimination of vincristine. Consequently, genetic polymorphisms in cytochrome P450 (P450) expression may contribute to the interindividual variability in clinical response, but the contributions of individual P450s and the primary pathways of vincristine metabolism have not been defined. In the present study, vincristine was incubated with a library of cDNA-expressed P450s, and the major oxidative metabolites were identified. CYP3A4 and CYP3A5 were the only P450s to support substantial loss of parent drug and formation of the previously unidentified, major metabolite (M1). The structure of M1, arising as a result of an oxidative cleavage of the piperidine ring of the dihydro-hydroxycatharanthine unit of vincristine, was conclusively established after conversion to suitable derivatives followed by spectroscopic analysis, and a new pathway for vincristine metabolism is proposed. CYP3A5 was more efficient in catalyzing the formation of M1 compared with CYP3A4 (9-to 14-fold higher intrinsic clearance for CYP3A5). The formation of M1 was stimulated (3-fold) by the presence of coexpressed cytochrome b 5 , but the relative efficiencies of M1 formation by CYP3A4 and CYP3A5 were unaffected. Our findings demonstrate that in contrast to most CYP3A biotransformations, the oxidation of vincristine is considerably more efficient with CYP3A5 than with CYP3A4. We conclude that common genetic polymorphisms in CYP3A5 expression may contribute to the interindividual variability in the systemic elimination of vincristine.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 52%

Selective Metabolism of Vincristine in Vitro by Cyp3a5

Dennison¹,

Kulanthaivel²,

Barbuch³

et al. 2006

Drug Metab Dispos

152

117

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“…There are numerous case reports in the literature, documenting greater neurotoxicity when itraconazole is prescribed during vinca alkaloid administration. [87][88][89][90][91] Cyclophosphamide, a common component of HSCT preparative regimens, is a prodrug that needs to undergo metabolism by CYP enzymes to produce the alkylator species required for its antineoplastic effect. The CYPs most involved in this process are CYP3A4 and CP2C9.…”

Section: Fluconazolementioning

confidence: 99%

Drug interactions in the hematopoietic stem cell transplant (HSCT) recipient: what every transplanter needs to know

Leather

2003

Bone Marrow Transplant

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Summary:Pharmacokinetic drug interactions among hematopoietic stem cell transplant recipients can result in either increases in serum concentrations of medications, which may lead to enhanced toxicity; or reduced serum concentrations, which can lead to treatment failure and the emergence of post transplant complications. The use of drugs that have a narrow therapeutic index, such as cyclosporine/tacrolimus (calcineurin inhibitors), increases the significance of these interactions when they occur. This report will review the clinical data evaluating the drug interactions of relevance to HSCT clinical practice, focusing on the pharmacokinetic interactions, and provides recommendations for managing these interactions to avoid both toxicity and treatment failure. Keywords: drug interactions; cytochrome P450; cyclosporine; tacrolimus; pharmacokinetic; CYP3A4; azoles A drug interaction is best defined as 'the possibility that one drug may alter the intensity of pharmacological effects of another drug that is given concurrently'. This results in either enhanced activity of the affected drug, which may lead to toxicity, or reduced activity of the affected drug, leading to therapeutic failure. It is also possible that there may be the appearance of a new effect that is not seen with either drug alone, for example, caspofungin and cyclosporine coadministration leading to elevated liver function tests. Drug interactions can be categorized as being either pharmacokinetic (PK) or pharmacodynamic in nature, and the remainder of this review will focus on PK interactions. Pharmacokinetic drug interactions -what are they?Pharmacokinetic drug interactions influence the disposition of the drug in the body. When drugs are ingested, they undergo several processes to produce an end effect, including absorption, distribution, metabolism, and excretion. Interactions between two or more drugs may affect any of these phases, including the modulation of hepatic drug biotransformation, renal clearance, altered distribution, or changes in plasma protein binding. The most clinically relevant mechanisms of PK drug interactions relate to metabolism and elimination of drugs from the body, and involve the cytochrome P450 (CYP) enzymes and the transporter P-glycoprotein at the hepatic and intestinal levels, and glomerular filtration and tubular secretion at the renal level. Cytochrome microsomal enzyme systemThe CYP microsomal enzyme system is a family of hemoproteins that is responsible for the oxidative biotransformation of endogenous substrates and xenobiotics. CYPs are expressed in several tissues, with the main drug metabolizing CYPs concentrated in the liver, with lower expression in the lungs, kidneys, intestines, and brain.1 Of the several different CYP isoforms identified, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 have the greatest involvement in drug metabolism. An extensive list of drugs metabolized by the various isoenzymes is outlined in Table 1. 2 The majority of oxidatively biotransformed drugs are metabolized, at least in part, ...

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“…According to the results of the present study, the use of ITC as prophylactic agent seems feasible and safe in pediatric patients, who actually did not receive vinca alkaloids or high-dose cyclophosphamide as antineoplastic agent [23,26] and who were able to tolerate a daily dose of 8-10 mg kg −1 day −1 (divided into two doses). Plasma trough concentrations (aim: >0.5 mg/l) are important for targeting the dose and represent a surrogate marker for systemic exposure to ITC and its active metabolite.…”

Section: Discussionmentioning

confidence: 68%

“…The most important interaction is the increased neurotoxicity of vinca alkaloids if ITC is coadministered [23,26]. Our regimen to stop ITC at least 5 days before the administration of vincristine seems to be safe, but it leaves the question unanswered what to do next, as protective ITC concentrations will fall below 0.5 mg/l in a few days (data on file, not shown).…”

Section: Adverse Effects and Possible Interactionsmentioning

confidence: 93%

Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants

Simon

Besuden

Vezmar

et al. 2006

Support Care Cancer

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Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies

Abstract: The extent and consistency of adverse effects documented in this study support the recommendation that concurrent administration of vincristine and itraconazole should be avoided.

Cited by 28 publications

References 11 publications

Selective Metabolism of Vincristine in Vitro by Cyp3a5

Selective Metabolism of Vincristine in Vitro by Cyp3a5

Drug interactions in the hematopoietic stem cell transplant (HSCT) recipient: what every transplanter needs to know

Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants

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