Increased urinary excretion of carnitine in patients treated with cisplatin

Heuberger, W; Berardi, Simona; Jacky, E; Pey, Pascaline; Krähenbühl, Stephan

doi:10.1007/s002280050504

Cited by 64 publications

(57 citation statements)

References 14 publications

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“…Furthermore, heterozygosity for OCTN2 mutations in humans is associated with an intermediate carnitine-deficiency phenotype, suggesting that even partial loss of transporter function may be detrimental. In this context, it is particularly noteworthy that, in a previous study involving a small cohort of adult patients, treatment with cisplatin was associated with a significant increase in the urinary excretion of carnitine, which eventually normalized about 7 days after discontinuing therapy (Heuberger et al, 1998). Similar observations have been made in patients undergoing combination chemotherapy with ifosfamide-doxorubicin-cisplatin (Hockenberry et al, 2009), paclitaxel-carboplatin, or vinorelbine-carboplatin (Mancinelli et al, 2007).…”

Section: Platinum Chemotherapeuticssupporting

confidence: 62%

Uptake Carriers and Oncology Drug Safety

Sprowl

Sparreboom

2013

Drug Metab Dispos

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Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics in multiple tissues. Many of these transporters are highly expressed in the gastrointestinal tract, liver, and kidney and are considered to be of particular importance in governing drug absorption, elimination, and cellular sensitivity of specific organs to a wide variety of oncology drugs. Although the majority of studies on the interaction of oncology drugs with SLC have been restricted to the use of exploratory in vitro model systems, emerging evidence suggests that several SLCs, including OCT2 and OATP1B1, contribute to clinically important phenotypes associated with those agents. Recent literature has indicated that modulation of SLC activity may result in drug-drug interactions, and genetic polymorphisms in SLC genes have been described that can affect the handling of substrates. Alteration of SLC function by either of these mechanisms has been demonstrated to contribute to interindividual variability in the pharmacokinetics and toxicity associated with several oncology drugs. In this report, we provide an update on this rapidly emerging field.

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Section: Platinum Chemotherapeuticssupporting

confidence: 62%

Uptake Carriers and Oncology Drug Safety

Sprowl

Sparreboom

2013

Drug Metab Dispos

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“…In the majority of patients, this side-effect significantly improved after LC supplementation which was well tolerated and did not affect anti-cancer therapeutic efficacy. These data suggest that chemotherapy-induced damage of the carnitine system and secondary deficiency of the molecule (Dodson et al, 1989;Heuberger et al, 1998;Marthaler et al, 1999;Peluso et al, 2000) may cause fatigue due to impaired energy metabolism (Peluso et al, 2000). It therefore follows that restoration of the carnitine pool may alleviate this symptom (Brass et al, 2001).…”

Section: Discussionmentioning

confidence: 96%

“…Chemotherapy causes dysfunction of enzymes involved in the transport and trafficking of carnitines (Peluso et al, 2000) and, in addition, ifosfamide and cisplatin induce increased urinary excretion of these molecules (Dodson et al, 1989;Marthaler et al, 1999;Heuberger et al, 1998). These effects may worsen the dysmetabolic syndrome associated with cancer (Tisdale, 1997) and increase side-effects of chemotherapy, like fatigue (Tisdale, 1997;Portenoy and Itri, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Also, reduction of tumour burden in response to the anticancer treatment may alleviate fatigue. The urinary excretion of carnitine persists for several days after chemotherapy and this clearance returns to normal values 7 days after the administration of cisplatin (Heuberger et al, 1998). However, even in the presence of carnitine deficiency, patients may restore their carnitine pool by food intake or endogen production, and urinary loss may not be sufficient to cause a symptomatic deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…Chemotherapy causes dysfunction of the carnitine system, which may contribute to a condition of asthenia due to the impaired energy metabolism (Breitkreutz et al, 2000;Peluso et al, 2000). Ifosfamide and cisplatin alter major enzymatic pathways and they cause carnitine secondary deficiency after increasing urinary excretion of the molecule (Dodson et al, 1989;Heuberger et al, 1998;Marthaler et al, 1999).…”

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confidence: 99%

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Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients

Graziano

Bisonni²,

Catalano³

et al. 2002

Br J Cancer

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Ifosfamide and cisplatin cause urinary loss of carnitine, which is a fundamental molecule for energy production in mammalian cells. We investigated whether restoration of the carnitine pool might improve chemotherapy-induced fatigue in non-anaemic cancer patients. Consecutive patients with low plasma carnitine levels who experienced fatigue during chemotherapy were considered eligible for study entry. Patients were excluded if they had anaemia or other conditions thought to be causing asthenia. Fatigue was assessed by the Functional Assessment of Cancer Therapy-Fatigue quality of life questionnaire. Treatment consisted of oral levocarnitine 4 g daily, for 7 days. Fifty patients were enrolled; chemotherapy was cisplatin-based in 44 patients and ifosfamide-based in six patients. In the whole group, baseline mean Functional Assessment of Cancer Therapy-Fatigue score was 19.7 (±6.4; standard deviation) and the mean plasma carnitine value was 20.9 μ M (±6.8; standard deviation). After 1 week, fatigue ameliorated in 45 patients and the mean Functional Assessment of Cancer Therapy-Fatigue score was 34.9 (±5.4; standard deviation) ( P <.001). All patients achieved normal plasma carnitine levels. Patients maintained the improved Functional Assessment of Cancer Therapy-Fatigue score until the next cycle of chemotherapy. In selected patients, levocarnitine supplementation may be effective in alleviating chemotherapy-induced fatigue. This compound deserves further investigations in a randomised, placebo-controlled study. British Journal of Cancer (2002) 86 , 1854–1857. doi: 10.1038/sj.bjc.6600413 www.bjcancer.com © 2002 Cancer Research UK

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Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system

et al. 2000

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An efficient regulation of fuel metabolism in response to internal and environmental stimuli is a vital task that requires an intact carnitine system. The carnitine system, comprehensive of carnitine, its derivatives, and proteins involved in its transformation and transport, is indispensable for glucose and lipid metabolism in cells. Two major functions have been identified for the carnitine system: (1) to facilitate entry of long-chain fatty acids into mitochondria for their utilization in energy-generating processes; (2) to facilitate removal from mitochondria of short-chain and medium-chain fatty acids that accumulate as a result of normal and abnormal metabolism. In cancer patients, abnormalities of tumor tissue as well as nontumor tissue metabolism have been observed. Such abnormalities are supposed to contribute to deterioration of clinical status of patients, or might induce cancerogenesis by themselves. The carnitine system appears abnormally expressed both in tumor tissue, in such a way as to greatly reduce fatty acid beta-oxidation, and in nontumor tissue. In this view, the study of the carnitine system represents a tool to understand the molecular basis underlying the metabolism in normal and cancer cells. Some important anticancer drugs contribute to dysfunction of the carnitine system in nontumor tissues, which is reversed by carnitine treatment, without affecting anticancer therapeutic efficacy. In conclusion, a more complex approach to mechanisms that underlie tumor growth, which takes into account the altered metabolic pathways in cancer disease, could represent a challenge for the future of cancer research.

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Increased urinary excretion of carnitine in patients treated with cisplatin

Cited by 64 publications

References 14 publications

Uptake Carriers and Oncology Drug Safety

Uptake Carriers and Oncology Drug Safety

Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients

Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system

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