Legal Medicine 16 (2014) 178–179
Contents lists available at ScienceDirect
Legal Medicine journal homepage: www.elsevier.com/locate/legalmed
Letter to the Editor Concentrations of basic drugs in postmortem blood require careful evaluation
Dear Editor, I read with great interest the article recently published in Legal Medicine by Hashiyada et al. [1], in which an unusually high concentration of bisoprolol was identified in a blood sample (176 ng/mL) obtained from a woman 1.5 days after she died from acute heart failure as a result of being erroneously administered 10 mg of oral bisoprolol. Based on the reported data [2,3], they claimed that the maximum blood concentration after oral administration of 10 mg of bisoprolol is usually around 50 ng/mL for most patients, and around 90 ng/mL for patients with severe chronic heart failure. They investigated genetic polymorphisms of cytochrome P450 (CYP) 2D6 and CYP3A4, both of which metabolize bisoprolol [4], in their patient, and found that, although the CYP3A4 gene had the wild-type allele producing normal enzyme activity, CYP2D6 gene showed mutations associated with a 50% reduction in enzyme activity [5,6]. In addition, they confirmed the co-existence of chlorpheniramine, clotiazepam and diphenhydramine in the patient by qualitative analysis; clotiazepam is metabolized by CYP3A4 [7], and chlorpheniramine and diphenhydramine are metabolized by CYP2D6 [8,9]. Competitive inhibition of bisoprolol metabolism by those substances at the relevant CYP enzymes, although unmentioned in the article, should therefore also be considered, after quantitative analyses of the substances, as another possible cause of the high bisoprolol concentration. However, the pharmacokinetics of bisoprolol are reportedly minimally affected by hepatic impairment [3], while being very much affected by renal impairment [3]. Given that their patient apparently had no history of renal disease, the CYP2D6 polymorphism and possible metabolic inhibition of bisoprolol does not adequately explain the high blood concentration of bisoprolol. Although the authors believed that 176 ng/mL was inexplicably high considering the oral administration of only 10 mg of bisoprolol, they seem not to have taken into account the effects of postmortem redistribution and sampling methods on postmortem blood concentrations. Basic bisoprolol has a relatively large volume of distribution, and high levels accumulate in the lungs and liver [10,11]. Bisoprolol would thus be redistributed postmortem from the lungs and liver and accumulate in blood in the heart and inferior vena cava, respectively, like other basic drugs [12,13]. The source of the blood sample for bisoprolol quantification was also unclear. Was it collected from the external iliac vein like blood samples used to screen for coexisting drugs? If so, was the blood sampled after clamping the central side of the vein? In my experience, basic drug concentrations in external iliac venous blood, although usually similar to those in femoral venous blood, can be high due to mixing with blood from the inferior vena cava http://dx.doi.org/10.1016/j.legalmed.2014.02.002 1344-6223/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
if sampled before the central side of the vein is clamped. Moreover, levels are rarely high when clamping precedes sampling [14]; postmortem blood movement in the vessels caused by inspecting and moving the body before autopsy would be partially responsible for this phenomenon. Undoubtedly, if bisoprolol was quantified in cardiac blood samples, postmortem redistribution from the lungs should be taken into consideration, as it is for other basic drugs [13]. Regardless, drug toxicity must not be defined according to findings from only one blood sample. Rather, it should at the very least be based on results using blood collected from the left and right cardiac chambers and femoral vein [15]. References [1] Hashiyada M, Usui K, Hayashizaki Y, Hosoya T, Igari Y, Sakai J, et al. Unexpectedly high blood concentration of bisoprolol after an incorrect prescription: a case report. Legal Med 2013;15:103–5. [2] Drugs Interview Form. Maintate. Pharmaceuticals and Medical Devices Agency. http://www.info.pmda.go.jp/ [in Japanese]. [3] de Groote P, Ennezat PV, Mouquet F. Bisoprolol in the treatment of chronic heart failure. Vasc Heart Risk Manag 2007;3:431–9. [4] Horikiri Y, Suzuki T, Mizobe M. Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci 1998;87:289–94. [5] Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452–9. [6] Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos 1999;27:385–8. [7] Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A. Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs. Biol Pharm Bull 2005;28:1711–6. [8] de Leon J, Nikoloff DM. Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports. CNA Spectr 2008;13:133–5. [9] Hamelin BA, Bouayad A, Drolet B, Gravel A, Turgeon J. In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists. Drug Metab Dispo 1998;26:536–9. [10] Bühring KU, Sailer H, Faro H-P, Leopold G, Pabst J, Garbe A. Pharmacokinetics and metabolism of bisoprolol-14C in three animal species and in humans. J Cardiovasc Pharmacol 1986;8:S21–8. [11] Li G, Wang K, Chen R, Zhao H, Yang J, Zheng Q. Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling. Acta Pharmacol Sin 2012;33:1359–71. [12] Hilberg T, Bugge A, Beylich K-M, Ingum J, BjØrneboe A, MØrland J. An animal model of postmortem amitriptyline redistribution. J Forensic Sci 1993;38:81–90. [13] Moriya F, Hashimoto Y. Redistribution of basic drugs into cardiac blood from surrounding tissues during early-stages postmortem. J Forensic Sci 1999;44:10–6. [14] Moriya F, Hashimoto Y. Distribution of free and conjugated morphine in body fluids and tissues in a fatal heroin overdose: is conjugated morphine stable in postmortem specimens? J Forensic Sci 1996;42:736–40. [15] Moriya F, Hashimoto Y. Criteria for judging whether postmortem blood drug concentrations can be used for toxicologic evaluation. Legal Med 2000;2:143–51.
Letter to the Editor / Legal Medicine 16 (2014) 178–179
179
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Fumio Moriya Department of Nursing, Faculty of Health and Medicine, Kawasaki University of Medical Welfare, Matsushima 288, Kurashiki, Okayama 701-0193, Japan Department of Legal Medicine, Graduate School of Medicine, Dentistry and Pharmacy, Okayama University, Shikata-cho 2-5-1, Kita-ku, Okayama 700-8558, Japan ⇑ Tel.: +81 86 462 1111; fax: +81 86 464 1109. E-mail address: [email protected] Available online 13 February 2014
Contents lists available at ScienceDirect
Legal Medicine journal homepage: www.elsevier.com/locate/legalmed
Letter to the Editor Concentrations of basic drugs in postmortem blood require careful evaluation
Dear Editor, I read with great interest the article recently published in Legal Medicine by Hashiyada et al. [1], in which an unusually high concentration of bisoprolol was identified in a blood sample (176 ng/mL) obtained from a woman 1.5 days after she died from acute heart failure as a result of being erroneously administered 10 mg of oral bisoprolol. Based on the reported data [2,3], they claimed that the maximum blood concentration after oral administration of 10 mg of bisoprolol is usually around 50 ng/mL for most patients, and around 90 ng/mL for patients with severe chronic heart failure. They investigated genetic polymorphisms of cytochrome P450 (CYP) 2D6 and CYP3A4, both of which metabolize bisoprolol [4], in their patient, and found that, although the CYP3A4 gene had the wild-type allele producing normal enzyme activity, CYP2D6 gene showed mutations associated with a 50% reduction in enzyme activity [5,6]. In addition, they confirmed the co-existence of chlorpheniramine, clotiazepam and diphenhydramine in the patient by qualitative analysis; clotiazepam is metabolized by CYP3A4 [7], and chlorpheniramine and diphenhydramine are metabolized by CYP2D6 [8,9]. Competitive inhibition of bisoprolol metabolism by those substances at the relevant CYP enzymes, although unmentioned in the article, should therefore also be considered, after quantitative analyses of the substances, as another possible cause of the high bisoprolol concentration. However, the pharmacokinetics of bisoprolol are reportedly minimally affected by hepatic impairment [3], while being very much affected by renal impairment [3]. Given that their patient apparently had no history of renal disease, the CYP2D6 polymorphism and possible metabolic inhibition of bisoprolol does not adequately explain the high blood concentration of bisoprolol. Although the authors believed that 176 ng/mL was inexplicably high considering the oral administration of only 10 mg of bisoprolol, they seem not to have taken into account the effects of postmortem redistribution and sampling methods on postmortem blood concentrations. Basic bisoprolol has a relatively large volume of distribution, and high levels accumulate in the lungs and liver [10,11]. Bisoprolol would thus be redistributed postmortem from the lungs and liver and accumulate in blood in the heart and inferior vena cava, respectively, like other basic drugs [12,13]. The source of the blood sample for bisoprolol quantification was also unclear. Was it collected from the external iliac vein like blood samples used to screen for coexisting drugs? If so, was the blood sampled after clamping the central side of the vein? In my experience, basic drug concentrations in external iliac venous blood, although usually similar to those in femoral venous blood, can be high due to mixing with blood from the inferior vena cava http://dx.doi.org/10.1016/j.legalmed.2014.02.002 1344-6223/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
if sampled before the central side of the vein is clamped. Moreover, levels are rarely high when clamping precedes sampling [14]; postmortem blood movement in the vessels caused by inspecting and moving the body before autopsy would be partially responsible for this phenomenon. Undoubtedly, if bisoprolol was quantified in cardiac blood samples, postmortem redistribution from the lungs should be taken into consideration, as it is for other basic drugs [13]. Regardless, drug toxicity must not be defined according to findings from only one blood sample. Rather, it should at the very least be based on results using blood collected from the left and right cardiac chambers and femoral vein [15]. References [1] Hashiyada M, Usui K, Hayashizaki Y, Hosoya T, Igari Y, Sakai J, et al. Unexpectedly high blood concentration of bisoprolol after an incorrect prescription: a case report. Legal Med 2013;15:103–5. [2] Drugs Interview Form. Maintate. Pharmaceuticals and Medical Devices Agency. http://www.info.pmda.go.jp/ [in Japanese]. [3] de Groote P, Ennezat PV, Mouquet F. Bisoprolol in the treatment of chronic heart failure. Vasc Heart Risk Manag 2007;3:431–9. [4] Horikiri Y, Suzuki T, Mizobe M. Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci 1998;87:289–94. [5] Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452–9. [6] Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos 1999;27:385–8. [7] Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A. Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs. Biol Pharm Bull 2005;28:1711–6. [8] de Leon J, Nikoloff DM. Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports. CNA Spectr 2008;13:133–5. [9] Hamelin BA, Bouayad A, Drolet B, Gravel A, Turgeon J. In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists. Drug Metab Dispo 1998;26:536–9. [10] Bühring KU, Sailer H, Faro H-P, Leopold G, Pabst J, Garbe A. Pharmacokinetics and metabolism of bisoprolol-14C in three animal species and in humans. J Cardiovasc Pharmacol 1986;8:S21–8. [11] Li G, Wang K, Chen R, Zhao H, Yang J, Zheng Q. Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling. Acta Pharmacol Sin 2012;33:1359–71. [12] Hilberg T, Bugge A, Beylich K-M, Ingum J, BjØrneboe A, MØrland J. An animal model of postmortem amitriptyline redistribution. J Forensic Sci 1993;38:81–90. [13] Moriya F, Hashimoto Y. Redistribution of basic drugs into cardiac blood from surrounding tissues during early-stages postmortem. J Forensic Sci 1999;44:10–6. [14] Moriya F, Hashimoto Y. Distribution of free and conjugated morphine in body fluids and tissues in a fatal heroin overdose: is conjugated morphine stable in postmortem specimens? J Forensic Sci 1996;42:736–40. [15] Moriya F, Hashimoto Y. Criteria for judging whether postmortem blood drug concentrations can be used for toxicologic evaluation. Legal Med 2000;2:143–51.
Letter to the Editor / Legal Medicine 16 (2014) 178–179
179
⇑
Fumio Moriya Department of Nursing, Faculty of Health and Medicine, Kawasaki University of Medical Welfare, Matsushima 288, Kurashiki, Okayama 701-0193, Japan Department of Legal Medicine, Graduate School of Medicine, Dentistry and Pharmacy, Okayama University, Shikata-cho 2-5-1, Kita-ku, Okayama 700-8558, Japan ⇑ Tel.: +81 86 462 1111; fax: +81 86 464 1109. E-mail address: [email protected] Available online 13 February 2014
