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. 2016 Apr;17(6):547-59.
doi: 10.2217/pgs-2015-0008. Epub 2016 Apr 5.

Pharmacokinetics and pharmacogenomics of β-lactam-induced neutropenia

Andrea Hahn  1   2 , Tsuyoshi Fukuda  3   4 , David Hahn  3 , Tomoyuki Mizuno  3 , Robert W Frenck Jr  4   5 , Alexander A Vinks  3   4
Affiliations

Pharmacokinetics and pharmacogenomics of β-lactam-induced neutropenia

Andrea Hahn et al. Pharmacogenomics. 2016 Apr.

Abstract

Aim: Determine if individuals with β-lactam induced neutropenia have polymorphisms that impair function of MRP4 or OAT1/OAT3.

Methods: Subjects with β-lactam induced neutropenia were compared to controls for the presence of MRP4 and OAT1/OAT3 polymorphisms, estimated plasma trough concentrations and area under the curve.

Results: Subjects with a homozygous polymorphism at MRP4 3348 A to G were 5.3 times more likely to develop neutropenia (p = 0.171). No statistical differences were noted in pharmacokinetic parameters. Contingency analysis of children greater than 5 years of age showed neutropenia in subjects who were homozygous wild type at MRP4 3348 A to G was significantly associated with standard or high dosing (p = 0.03).

Conclusion: MRP4 3348 A to G should be further studied for potential contribution to the development of β-lactam induced neutropenia.

Keywords: MRP4; OAT; neutropenia; β-lactam.

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Conflict of interest statement

Financial & competing interests disclosure

The data presented in this manuscript were supported with federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development under a fellowship training grant (5 T32 HD069054) and by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH (8 UL1 TR000077-04). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Flow diagram of subjects included in study.
350 subjects were contacted for inclusion. 94 subjects were included in the study, of which 44 were cases and 54 were controls.
<b>Figure 2.</b>
Figure 2.. Distribution of genotypes comparing cases (n = 44) and controls (n = 54).
MRP4 is multidrug resistance protein 4. OAT is organic anion transporter. The bar graphs are normalized to 100% and the numbers represent the number of cases and/or controls that were homozygous for the wild type (homozygous WT), heterozygous or homozygous for the polymorphism (homozygous SNP). WT: Wild type.
<b>Figure 3.</b>
Figure 3.. Contingency analysis of children >5 years of age for MRP4 3348 A>G.
Cases versus controls are compared using standard versus high dosing of β-lactam therapy. Standard dose for ceftriaxone was 50 mg/kg/day. High dose for ceftriaxone was 75–100 mg/kg/day. Standard dose for cefazolin was 75 mg/kg/day. High dose for cefazolin was 100–150 mg/kg/day. WT: Wild type.
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References

    1. Neftel KA, Hauser SP, Muller MR. Inhibition of granulopoiesis in vivo and in vitro by beta-lactam antibiotics. J. Infect. Dis. 1985;152(1):90–98. - PubMed

    2. • This study highlights the relationship between beta lactam antibiotics and the development of neutropenia.

    1. Andres E, Maloisel F. Idiosyncratic drug-induced agranulocytosis or acute neutropenia. Curr. Opin. Hematol. 2008;15(1):15–21. - PubMed
    1. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann. Intern. Med. 2007;146(9):657–665. - PubMed
    1. Neftel KA, Muller MR, Widmer U, Hugin AW. Beta-lactam antibiotics inhibit human in vitro granulopoiesis and proliferation of some other cell types. Cell Biol. Toxicol. 1986;2(4):513–521. - PubMed
    1. Neftel KA, Hubscher U. Effects of beta-lactam antibiotics on proliferating eucaryotic cells. Antimicrob. Agents Chemother. 1987;31(11):1657–1661. - PMC - PubMed

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