Bart A W Jacobs1,2, Nikol Snoeren3, Morsal Samim3, Hilde Rosing2, Niels de Vries2, Maarten J Deenen1, Jos H Beijnen2,4, Jan H M Schellens1,4, Miriam Koopman5, Richard van Hillegersberg6. 1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. 2. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. 3. Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. 4. Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmaco-epidemiology and Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands. 5. Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. 6. Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. r.vanhillegersberg@umcutrecht.nl.
Abstract
PURPOSE: The dihydrouracil (DHU):uracil (U) plasma ratio is a promising marker for identification of dihydropyrimidine dehydrogenase (DPD)-deficient patients. The objective of this study was to determine the effect of liver resection on the DHU:U plasma ratio in patients with colorectal liver metastases (CRLM). METHODS: An observational study was performed in which DHU:U plasma ratios in patients with CRLM were analyzed prior to and 1 day after liver resection. In addition, the DHU:U plasma ratio was quantified in six additional patients 4-8 weeks after liver resection to explore long-term effects on the DHU:U plasma ratio. Quantification of U and DHU plasma levels was performed using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay. RESULTS: The median (range) DHU:U plasma ratio in 15 patients prior to liver resection was 10.7 (2.6-14.4) and was significantly reduced to 5.5 (< quantification limit (LLOQ-10.5) 1 day after resection (p = 0.0026). This reduction was caused by a decrease in DHU plasma levels from 112.0 (79.8-153) ng/mL to 41.2 (< LLOQ-160) ng/mL 1 day after resection (p = 0.0004). Recovery of the DHU:U plasma ratio occurred 4-8 weeks after liver resection, which was shown by a median (range) DHU:U plasma ratio in six patients of 9.1 (6.9-14.5). CONCLUSION: Liver resection leads to very low DHU:U plasma ratios 1 day after liver resection, which is possibly caused by a reduction in DPD activity. Quantification of the DHU:U plasma ratios directly after liver resection could lead to false-positive identification of DPD deficiency and is therefore not advised.
PURPOSE: The dihydrouracil (DHU):uracil (U) plasma ratio is a promising marker for identification of dihydropyrimidine dehydrogenase (DPD)-deficientpatients. The objective of this study was to determine the effect of liver resection on the DHU:U plasma ratio in patients with colorectal liver metastases (CRLM). METHODS: An observational study was performed in which DHU:U plasma ratios in patients with CRLM were analyzed prior to and 1 day after liver resection. In addition, the DHU:U plasma ratio was quantified in six additional patients 4-8 weeks after liver resection to explore long-term effects on the DHU:U plasma ratio. Quantification of U and DHU plasma levels was performed using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay. RESULTS: The median (range) DHU:U plasma ratio in 15 patients prior to liver resection was 10.7 (2.6-14.4) and was significantly reduced to 5.5 (< quantification limit (LLOQ-10.5) 1 day after resection (p = 0.0026). This reduction was caused by a decrease in DHU plasma levels from 112.0 (79.8-153) ng/mL to 41.2 (< LLOQ-160) ng/mL 1 day after resection (p = 0.0004). Recovery of the DHU:U plasma ratio occurred 4-8 weeks after liver resection, which was shown by a median (range) DHU:U plasma ratio in six patients of 9.1 (6.9-14.5). CONCLUSION: Liver resection leads to very low DHU:U plasma ratios 1 day after liver resection, which is possibly caused by a reduction in DPD activity. Quantification of the DHU:U plasma ratios directly after liver resection could lead to false-positive identification of DPD deficiency and is therefore not advised.
Authors: Bart A W Jacobs; Maarten J Deenen; Dick Pluim; J G Coen van Hasselt; Martin D Krähenbühl; Robin M J M van Geel; Niels de Vries; Hilde Rosing; Didier Meulendijks; Artur M Burylo; Annemieke Cats; Jos H Beijnen; Alwin D R Huitema; Jan H M Schellens Journal: Br J Clin Pharmacol Date: 2016-06-03 Impact factor: 4.335
Authors: Dick Pluim; Bart A W Jacobs; Maarten J Deenen; Anneloes E M Ruijter; Robin M J M van Geel; Artur M Burylo; Didier Meulendijks; Jos H Beijnen; Jan H M Schellens Journal: Bioanalysis Date: 2015 Impact factor: 2.681
Authors: Zhi Wei Zhou; Guo Qiang Wang; De Sen Wan; Zhen Hai Lu; Ying Bo Chen; Su Li; Gong Chen; Zhi Zhong Pan Journal: Chemotherapy Date: 2007-02-16 Impact factor: 2.544
Authors: Nikol Snoeren; Richard van Hillegersberg; Sander B Schouten; Andre M Bergman; Erikv van Werkhoven; Otilia Dalesio; Rob A E M Tollenaar; Henk M Verheul; Joost van der Sijp; Inne H M Borel Rinkes; E E Voest Journal: Neoplasia Date: 2017-01-12 Impact factor: 5.715
Authors: A Loganayagam; M Arenas Hernandez; A Corrigan; L Fairbanks; C M Lewis; P Harper; N Maisey; P Ross; J D Sanderson; A M Marinaki Journal: Br J Cancer Date: 2013-06-04 Impact factor: 7.640