- Email: [email protected]
Response to “Intrauterine exposure to thiopurines”
Reproductive Toxicology 33 (2012) 125
Contents lists available at SciVerse ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Letter to the Editor Response to “Intrauterine exposure to thiopurines” We would like to thank Jharap et al. for their interest in our paper [1]. We agree that the generalizability of our placental perfusion findings from this study is limited to the parent drug, 6-MP. Our study did not observe 6-TGNs in the fetal perfusate during the course of the perfusion and Jharap et al. state that this finding is contradictory to the observations in humans. The placental perfusion experiment is ideal to specifically investigate the mechanism of transfer across the human placenta since confounding metabolic and physiologic influences of maternal and/or fetal origin are eliminated [2]. Our study shows that the placenta has a limited capacity for bioactivation of 6-MP into its active metabolites and suggests that fetal levels of 6-TGNs result from transfer of maternally derived metabolites. Only free 6-TGNs are able to cross the placenta, and the bulk of these metabolites are located intracellularly. This localization likely explains the much lower levels of 6-TGNs found in umbilical cord blood compared to maternal blood [3]. Our study also detected low levels of 6-MMP produced by the placenta in the perfusate, whereas 6-MMP has not been observed in RBCs isolated from umbilical cord blood. The perfusion model does not incorporate RBC binding, fetal clearance or fetal distribution and these factors may explain this difference. Indeed, further studies into the mechanism of placental transfer of the metabolites would provide valuable data on this complex matter. Perfusion studies in combination with in vivo umbilical cord blood and maternal blood measurements can be used together to kinetically model placental drug transfer [2]. Together, these two experimental designs can be an invaluable source for predicting in utero drug exposure in pregnancy. The ongoing study by the Dutch Initiative on Crohn and Colitis will undoubtedly provide data that will contribute to our understanding of fetal exposure to thiopurines. Furthermore, in vivo data measuring 6-MP and its metabolites in umbilical cord blood
0890-6238/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.reprotox.2011.11.110
and maternal blood can guide placental perfusion experiments by reporting on clinically relevant concentrations in late gestation. Findings from our current perfusion experiments on 6-MP are consistent with observations seen in humans and support the recommendations by de Boer to monitor maternal thiopurine levels during pregnancy to limit fetal exposure [3]. References [1] Hutson JR, Lubetsky A, Walfisch A, Ballios BG, Garcia-Bournissen F, Koren G. The transfer of 6-mercaptopurine in the dually perfused human placenta. Reprod Toxicol 2011;32:349–53. [2] Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther 2011;90:67–76. [3] de Boer NK, Van Elburg RM, Wilhelm AJ, Remmink AJ, Van Vugt JM, Mulder CJ, et al. 6-Thioguanine for Crohn’s disease during pregnancy: thiopurine metabolite measurements in both mother and child. Scand J Gastroenterol 2005;40: 1374–7.
Janine R. Hutson a,b Gideon Koren a,b,∗ a Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada b Institute of Medical Science, University of Toronto, Toronto, Canada ∗ Corresponding author at: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. Tel.: +1 416 813 5781; fax: +1 416 813 7562. E-mail address: [email protected] (G. Koren)
12 October 2011 Available online 6 December 2011
Contents lists available at SciVerse ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Letter to the Editor Response to “Intrauterine exposure to thiopurines” We would like to thank Jharap et al. for their interest in our paper [1]. We agree that the generalizability of our placental perfusion findings from this study is limited to the parent drug, 6-MP. Our study did not observe 6-TGNs in the fetal perfusate during the course of the perfusion and Jharap et al. state that this finding is contradictory to the observations in humans. The placental perfusion experiment is ideal to specifically investigate the mechanism of transfer across the human placenta since confounding metabolic and physiologic influences of maternal and/or fetal origin are eliminated [2]. Our study shows that the placenta has a limited capacity for bioactivation of 6-MP into its active metabolites and suggests that fetal levels of 6-TGNs result from transfer of maternally derived metabolites. Only free 6-TGNs are able to cross the placenta, and the bulk of these metabolites are located intracellularly. This localization likely explains the much lower levels of 6-TGNs found in umbilical cord blood compared to maternal blood [3]. Our study also detected low levels of 6-MMP produced by the placenta in the perfusate, whereas 6-MMP has not been observed in RBCs isolated from umbilical cord blood. The perfusion model does not incorporate RBC binding, fetal clearance or fetal distribution and these factors may explain this difference. Indeed, further studies into the mechanism of placental transfer of the metabolites would provide valuable data on this complex matter. Perfusion studies in combination with in vivo umbilical cord blood and maternal blood measurements can be used together to kinetically model placental drug transfer [2]. Together, these two experimental designs can be an invaluable source for predicting in utero drug exposure in pregnancy. The ongoing study by the Dutch Initiative on Crohn and Colitis will undoubtedly provide data that will contribute to our understanding of fetal exposure to thiopurines. Furthermore, in vivo data measuring 6-MP and its metabolites in umbilical cord blood
0890-6238/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.reprotox.2011.11.110
and maternal blood can guide placental perfusion experiments by reporting on clinically relevant concentrations in late gestation. Findings from our current perfusion experiments on 6-MP are consistent with observations seen in humans and support the recommendations by de Boer to monitor maternal thiopurine levels during pregnancy to limit fetal exposure [3]. References [1] Hutson JR, Lubetsky A, Walfisch A, Ballios BG, Garcia-Bournissen F, Koren G. The transfer of 6-mercaptopurine in the dually perfused human placenta. Reprod Toxicol 2011;32:349–53. [2] Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther 2011;90:67–76. [3] de Boer NK, Van Elburg RM, Wilhelm AJ, Remmink AJ, Van Vugt JM, Mulder CJ, et al. 6-Thioguanine for Crohn’s disease during pregnancy: thiopurine metabolite measurements in both mother and child. Scand J Gastroenterol 2005;40: 1374–7.
Janine R. Hutson a,b Gideon Koren a,b,∗ a Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada b Institute of Medical Science, University of Toronto, Toronto, Canada ∗ Corresponding author at: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. Tel.: +1 416 813 5781; fax: +1 416 813 7562. E-mail address: [email protected] (G. Koren)
12 October 2011 Available online 6 December 2011