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Pharmacokinetics and Drug Metabolism in the Design and Interpretation of Developmental Toxicity Studies

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Risk Assessment of Prenatally-Induced Adverse Health Effects

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Abstract

A direct teratogenic effect will depend on the concentration-time relationship of the drug or its active metabolite in the placental-embryonic compartment during the sensitive stages of gestation. Pharmacokinetic studies are therefore important for the interpretation and design of teratogenicity experiments, particularly for the problem of species differences, and for attempts to extrapolate experimental findings to the human (“risk assessment”). Pharmacokinetic studies are also crucial in elucidating whether the parent drug or a metabolite is the proximate or ultimate toxic entity. Finally, it is shown that structure-activity studies can greatly benefit from pharmacokinetic experiments to demonstrate whether the teratogenicity of a substance is related to its intrinsic activity or to the extent of placental transfer or both.

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References

  • Barua AB, Olson JA (1989) Chemical synthesis of all-trans-[11-s3H ] retinoyl β-glucuronide and its metabolism in rats in vivo. Biochem J 263: 403–409.

    PubMed  CAS  Google Scholar 

  • Binkerd PE, Rowland JM, Nau H, Hendrickx AG (1988) Evaluation of valproic acid (VPA) developmental toxicity and phannacokinetics in Sprague-Dawley rats. Fund Appl Toxicol 11: 485–493.

    Article  CAS  Google Scholar 

  • Blaschke G, Kraft HP, Fickentscher K, Köhler F (1979) Chromatographische Raeemattrennung von Thalidomid und teratogene Wirkung. Drug Res 29: 1640–1642.

    CAS  Google Scholar 

  • Bonati M, Latini R, Tognoni G, Young JF, Garattini S (1984-85) Interspecies comparison of in vivo caffeine phannacokinetics in man, monkey, rabbit, rat, and mouse. Drug Metab Rev 15: 1355–1383.

    Article  PubMed  CAS  Google Scholar 

  • Creech Kraft J, Kochhar DM, Scott WJ, Nau H (1987) Low teratogenicity of 13-cis-retinoic acid (isotretinoin) in the mouse corresponds to low embryo concentrations during organogenesis: Comparison to the all-trans isomer. Toxicol Appl Pharmacol 87: 474–482.

    Article  Google Scholar 

  • Creech Kraft J, Löfberg B, Chahoud I, Bochert G, Nau H (1989) Teratogenicity and placental transfer of all-trans-, 13-cis-, 4-oxo-all-trans-and 4-oxo-13-cis-retinoic acid after administration of a low oral dose during organogenesis in mice. Toxicol Appl Pharmacol 100: 162–176.

    Article  Google Scholar 

  • Creech Kraft J, Slikker W, Bailey JR, Roberts LG, Fischer B, Wittfoht W, Nau H (1990) Plasma phannacokinetics and metabolism of 13-cis and all-trans-retinoic acid in the cynomolgus monkey and the identification of 13-cis and all-trans-retinoyl-ß-glucuronides: A comparison to one human case study with isotretinoin. Drug Metab Disp 19: 317–324.

    Google Scholar 

  • Dencker L (1987) Transfer of drugs to the embryo and fetus after placentation. In: Nau H, Scott WJ (eds) Pharmacokinetics in teratogenesis. Vol. I. Interspecies comparison and maternal embryonic fetal drug transfer. CRC Press, Boca Raton, pp 55–70.

    Google Scholar 

  • Eckhoff C, Löfberg B, Chahoud I, Bochert G, Nau H (1989) Transplacental pharmacokinetics and teratogenicity of a single dose of retinol (vitamin A) during organogenesis in the mouse. Toxicol Lett 48: 171–184.

    Article  PubMed  CAS  Google Scholar 

  • Eckhoff C, Nau H (1990a) Identification and quantitation of all-trans-and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma. J Lipid Res 31: 1445–1454.

    PubMed  CAS  Google Scholar 

  • Eckhoff C, Nau H (1991) Vitamin A supplementation increases levels of retinoic acid compounds in human plasma: Possible implications for teratogenesis. Arch Toxicol 64: 502–503.

    Article  Google Scholar 

  • Eckhoff C, Wittfoht W, Nau H, Slikker W (1990b) Characterization of oxidized and glucuronidated metabolites of retinol in monkey plasma by thermospray liquid chromatography/mass spectrometry. Biomed Environm Mass Spectrom 19: 428–433.

    Article  CAS  Google Scholar 

  • Fabro S, Smith RL, Williams RT (1967) Toxicity and teratogenicity of optical isomers of thalidomide. Nature 215: 296.

    Article  PubMed  CAS  Google Scholar 

  • Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother 50: 219–245.

    CAS  Google Scholar 

  • Gordon GB, Spielberg SP, Blake DA, Balasubramanian V (1981) Thalidomide teratogenesis: Evidence for a toxic arene oxide metabolite. Proc Natl Acad Sci USA 78: 2545–2548.

    Article  PubMed  CAS  Google Scholar 

  • Hauck RS, Nau H (1989a) Zu den strukturellen Grundlagen der teratogenene Wirkung des Antiepileptikums Valproinsäure (VPA). Naturwissenschaften 76: 528–529.

    Article  PubMed  CAS  Google Scholar 

  • Hauck RS, Nau H (1989b) Asymmetric synthesis and enantioselective teratogenicity of 2-n-pro-pyl-4-pentenoic acid (4-en-VPA), an active metabolite of the anticonvulsant drug, valproic acid. Toxicol Lett 49: 41–48.

    Article  PubMed  CAS  Google Scholar 

  • Hauck RS, Wegner C, Blumtritt P, Fuhrhop JH, Nau H (1990) Asymmetric synthesis and teratogenic activity of (R)-and (S)-2-ethylhexanoic acid, a metabolite of the plasticizer di-(2-ethylhexyl)phthalate. Life Sci 46: 513–518.

    Article  PubMed  CAS  Google Scholar 

  • Heger W, Klug S, Schmahl HJ, Nau H, Merker HJ, Neubert D (1988) Embryotoxic effects of thalidomide derivatives on the non-human primate Callithrix jacchus. 3. Teratogenic potency of the EM 12 enantiomers. Arch Toxicol 62: 205–208.

    Article  PubMed  CAS  Google Scholar 

  • Helm FC, Frankus E, Friderichs E, Graudums I, Flohé L (1981) Comparative teratological investigation of compounds structurally and pharmacologically related to thalidomide. Drug Res 31: 941–949.

    CAS  Google Scholar 

  • Itami T, Kanoh S (1983) Studies on the pharmacological basis of fetal toxicity of drugs (IV). Effect of endotoxin and starvation on serum protein binding of salicylic acid in pregnant rats. Japan J Pharmacol 33: 1199–1204.

    Article  CAS  Google Scholar 

  • Jackson AJ, Schumacher HJ (1980) Identification of urinary metabolites of EM12 N-(2′,6′-Dioxopiperiden-3′-yl)-phthalimidine, a teratogenic analog of thalidomide in rats and rabbits. Can J Pharmaceut Sci 15: 21–23.

    CAS  Google Scholar 

  • Jäger-Roman E, Deichl A, Jakob S, Hartmann A-M, Koch S, Rating D, Steldinger R, Nau H, Helge H (1986) Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 108: 997–1004.

    Article  PubMed  Google Scholar 

  • Kistler A, Hummler H (1985) Teratogenesis and reproductive safety evaluation of the retinoid etretin (Ro 10-1670). Arch Toxicol 58: 50–56.

    Article  PubMed  CAS  Google Scholar 

  • Klug S, Lewandowski C, Zappel F, Merker HJ, Nau H, Neubert D (1990) Effects of valproic acid, some of its metabolites and analogues on prenatal development of rats in vitro and comparison with effects in vivo. Arch Toxicol 64: 545–553.

    Article  PubMed  CAS  Google Scholar 

  • Koch H (1981) Die Arenoxid-Hypothese der Thalidomid-Wirkung. Überlegungen zum molekularen Wirkungsmechanismus des “klassischen” Teratogens. Sci Pharm 49: 67–99.

    CAS  Google Scholar 

  • Kubow S, Wells PG (1989) In vitro bioactivation of phenytoin to a reactive free radical intermediate by prostaglandin synthetase, horse radish peroxidase, and thyroid peroxidase. Mol Pharmacol 35: 504–511.

    PubMed  CAS  Google Scholar 

  • Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW, Lott IT, Richard JM, Sun SC (1985) Retinoic acid embryopathy. New Engl J Med 313: 837–841.

    Article  PubMed  CAS  Google Scholar 

  • Löfberg B, Reiners J, Spielmann H, Nau H (1990) Teratogenicity of steady-state concentrations of etretinate and metabolite acitretin maintained in maternal plasma and embryo by intragastric infusion during organogenesis in the mouse: A possible model for the extended elimination phase in human therapy. Dev Pharmacol Therapeut 15: 45–51.

    Google Scholar 

  • Löscher W, Nau H, Marescaux C, Vergnes M (1984) Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models of epilepsy. Eur J Pharmacol 99: 211–218.

    Article  PubMed  Google Scholar 

  • Löscher W, Nau H (1985) Pharmacological evaluation of various metabolites and analogues of valproic acid. Neuropharm 24: 427–435.

    Article  Google Scholar 

  • Martz F, Failinger C, Blake DA (1977) Phenytoin teratogenesis: Correlation between embryopathic effect and covalent binding of putative arene oxide metabolite in gestational tissue. J Pharmacol Exp Ther 203: 231–239.

    PubMed  CAS  Google Scholar 

  • Mast TJ, Cukierski MA, Nau H, Hendrickx AG (1986) Predicting the human teratogenic potential of the anticonvulsant, valproic acid, from a non-human primate model. Toxicology 39: 111–119.

    Article  PubMed  CAS  Google Scholar 

  • Merker H-J, Heger W, Sames K, Stürje H, Neubert D (1988) Embryotoxic effects of thalidomide derivatives in the non-human primate Callithrix jacchus. I. Effects of 3-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidene (EM 12) on skeletal development. Arch Toxicol 61: 165–179.

    Article  PubMed  CAS  Google Scholar 

  • Mirkin BL, Singh S (1976) Placental transfer of pharmacologically active molecules. In: Mirkin BL (ed) Perinatal pharmacology and therapeutics, Academic Press, New York, San Francisco, London, pp 1–69.

    Google Scholar 

  • Nau H, Creech Kraft J, Eckhoff C, Löfberg B (1989) Interpretation of retinoid teratogenesis by transplacental pharmacokinetics. In: Reichert U, Shroot B (eds) Pharmacology of retinoids in the skin. Vol. 3, Karger, Basel, pp 165–173.

    Google Scholar 

  • Nau H, Helge H, Luck W (1984) Valproic acid in the perinatal period: Decreased maternal serum protein binding results in fetal accumulation and neonatal displacement of the drug and some metabolites. J Pediatr 104: 627–634.

    Article  PubMed  CAS  Google Scholar 

  • Nau H, Hendrickx AG (1987) Valproic acid teratogenesis. ISI Atl Sci Pharmacol pp 52-56.

    Google Scholar 

  • Nau H, Krauer B (1986) Serum protein binding of valproic acid in fetus-mother pairs throughout pregnancy: Correlation with oxytocin administration and albumin and free fatty acid concentrations. J Clin Pharmacol 26: 215–221.

    PubMed  CAS  Google Scholar 

  • Nau H, Löscher W, Schäfer H (1984) Anticonvulsant activity and embryotoxicity of valproic acid. Neurology 34: 400–401.

    PubMed  CAS  Google Scholar 

  • Nau H, Löscher W (1986) Pharmacologic evaluation of various metabolites and analogs of valproic acid: Teratogenic potencies in mice. Fund Appl Toxicol 6: 669–676.

    Article  CAS  Google Scholar 

  • Nau H, Löscher W (1984) Valproic acid and metabolites: Pharmacological and toxicological studies. Epilepsia 25(Suppl1): 14–22.

    Article  CAS  Google Scholar 

  • Nau H, Mirkin BL (1987) Fetal and maternal clinical pharmacokinetics. In: Avery’s drug treatment principles and practice of clinical pharmacology and therapeutics, 3rd Edition, ADIS Press, Auckland, pp 79–117.

    Google Scholar 

  • Nau H, Scott WJ (1987b) Teratogenicity of valproic acid and related substances in the mouse: Drug accumulation and pHi in the embryo during organogenesis and structure-activity considerations. Arch Toxicol(Suppl) 11: 128–139.

    CAS  Google Scholar 

  • Nau H, Scott WJ (1986) Weak acids may act as teratogens by accumulating in the basic milieu of the early mammalian embryo. Nature 323: 276–278.

    Article  PubMed  CAS  Google Scholar 

  • Nau H, Scott WJ (1987a) eds. Pharmacokinetics in Teratogenesis. Vol. I & II. Experimental Aspects In Vivo and In Vitro. Boca Raton, CRC Press.

    Google Scholar 

  • Nau H, Spielmann H (1983) Embryotoxicity testing of valproic acid. Lancet i: 763–764.

    Article  Google Scholar 

  • Nau H (1985a) Clinical pharmacokinetics in pregnancy and perinatology. I. Placental transfer and fetal side effects of local anaesthetic agents. Dev Pharmacol Ther 8: 149–181.

    PubMed  CAS  Google Scholar 

  • Nau H (1988) Pharmakokinetische Grundlagen der Teratogenität von Arzneimitteln. Internist 29: 179–192.

    PubMed  CAS  Google Scholar 

  • Nau H (1986a) Species differences in pharmacokinetics and drug teratogenesis. Environ Health Perspect 70: 113–129.

    Article  PubMed  CAS  Google Scholar 

  • Nau H (1985b) Teratogenic valproic acid concentrations: Infusion by implanted minipumps vs conventional injection regimen in the mouse. Toxicol Appl Pharmacol 80: 243–250.

    Article  PubMed  CAS  Google Scholar 

  • Nau H (1986b) Transfer of valproic acid and its main active unsaturated metabolite to the gestational tissue: Correlation with neural tube defect formation in the mouse. Teratology 33: 21–27.

    Article  PubMed  CAS  Google Scholar 

  • Nau H (1986c) Valproic acid teratogenicity in mice after various administration and phenobarbital-pretreatment regimens: The parent drug and not one of the metabolites assayed is implicated as teratogen. Fund Appl Toxicol 6: 662–668.

    Article  CAS  Google Scholar 

  • Neubert D, Chahoud I (1985) Significance of species and strain differences in pre-and perinatal toxicology. Acta histochem 31(Suppl): 23–35.

    CAS  Google Scholar 

  • Neubert D, Heger W, Merker H-J, Sames K, Meister R (1988) Embryotoxic effects of thalidomide derivatives in the non-human primate Callithrix jacchus. II. Elucidation of the susceptible period and of the variablility of embryonic stages. Arch Toxicol 61: 180–191.

    Article  PubMed  CAS  Google Scholar 

  • Roll R, Matthiaschk G (1983) Vergleichende Untersuchungen zur Embryotoxizitat von 2-Methyl-4-chlorphenoxyessigsäure, Mecoprop und Dichlorprop bei NMRI-Mäusen. Arzneim-Forsch/Drug Res 33: 1479–1483.

    CAS  Google Scholar 

  • Reiners J, Löfberg B, Creech Kraft J, Kochhar DM, Nau H (1988) Transplacental pharmacokinetics of teratogenic doses of etretinate and other aromatic retinoids in mice. Reprod Toxicol 2: 19–29.

    Article  PubMed  CAS  Google Scholar 

  • Robertson RT, Minsker DH, Bokelman DL, Durand G, Conquet P (1981) Potassium loss as a causative factor for skeletal malformations in rats produced by indacrinone: A new investigational loop diuretic. Toxicol Appl Pharmacol 60: 142–150.

    Article  PubMed  CAS  Google Scholar 

  • Sawada Y, Hanono M, Sugiyama Y, Iga T (1984) Prediction of the disposition of β-lactam antibiotics in humans from pharmacokinetic parameters in animals. J Pharmacokin Biopharmaceut 12: 241–261.

    Article  CAS  Google Scholar 

  • Schardein JL, Schwetz BA, Kenel MF (1985) Species sensitivities and prediction of teratogenic potential. Environ Health Perspect 61: 55–67.

    PubMed  CAS  Google Scholar 

  • Schmahl HJ, Heger W, Nau H (1989) The enantiomers of the teratogenic thalidomide analogue EM12. 2. Chemical stability, stereoselectivity of metabolism and renal excretion in the marmoset monkey. Toxicol Lett 45: 23–33.

    Article  PubMed  CAS  Google Scholar 

  • Schmahl HJ, Nau H, Neubert D (1988) The enantiomers of the teratogenic thalidomide analogue EMI. 1. Chiral inversion and plasma pharmacokinetics in the marmoset monkey. Arch Toxicol 62: 200–204.

    Article  PubMed  CAS  Google Scholar 

  • Schumacher HJ (1975) Chemical structure and teratogenic properties. In: Shepard TH, Miller JR, Marois (eds) Methods for detection of environmental agents that produce congenital malformations. Elsevier, Amsterdam, pp 65–77.

    Google Scholar 

  • Scott WJ, Fradkin R, Wilson JG (1977) Non-confirmation of thalidomide induced teratogenesis in rats and mice. Teratology 16: 333–336.

    Article  PubMed  CAS  Google Scholar 

  • Smith C (1987) Pharmacokinetics and toxicity testing: basic principles and pitfalls. In: Nau H, Scott WJ (eds) Pharmacokinetics in Teratogenesis. Vol. I. Interspecies comparison and maternal embryonic fetal drug transfer. CRC Press, Boca Raton, pp 107–122.

    Google Scholar 

  • Sterz H, Nothdurft H, Lexa P, Ockenfels H (1987) Teratologic studies on the Himalayan rabbit: new aspects of thalidomide-induced teratogenesis. Arch Toxicol 60: 376–381.

    Article  PubMed  CAS  Google Scholar 

  • Vorhees CV, Acuff-Smith KD, Weisenburger WP, Minck DR, Berry JS, Setchell KDR, Nau H (1991) Lack of teratogenieity of trans-2-ene-valproic acid compared to valproic acid in rats. Teratology 43: 583–590.

    Article  PubMed  CAS  Google Scholar 

  • Wells PG, Zubovits JT, Wong ST, Molinari LM, Ali S (1989) Modulation of phenytoin teratogenicity and embryonic covalent binding by acetylsalicylic acid, caffeic acid, and α-phenyl-n-t-butylnitrone: Implications for bioactivation by prostaglandin synthetase. Toxicol Appl Pharmacol 97: 192–202.

    Article  PubMed  CAS  Google Scholar 

  • Willhite CC, Shealy YF (1984) Amelioration of embryotoxicity by structural modification of the terminal group of cancer chemopreventive retinoids. J Natl Cancer Inst 72: 689–695.

    PubMed  CAS  Google Scholar 

  • Wilson JG, Ritter EJ, Scott WJ, Fradkin R (1977) Comparative distribution and embryotoxicity of acetylsalicylic acid in pregnant rats and rhesus monkeys. Toxicol Appl Pharmacol 41: 67–78.

    Article  PubMed  CAS  Google Scholar 

  • Zile MH, Cullum ME, Simpson RU, Barua AB, Swartz DA (1987) Induction of differentiation of human promyelocytic leukemia cell line HL-60 by retinoyl glucuronide, a biologically active metabolite of vitamin A. Proc Natl Acad Sci USA 84: 2208–2212.

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. Heinz Nau
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Editors and Affiliations

  1. Institut für Toxikologie und Embryopharmakologie, Universitätsklinikum Rudolf Virchow, Freie Universität Berlin, Garystrasse 5, W-1000, Berlin 33, Germany

    Diether Neubert

  2. Developmental Toxicology Division, US Environmental Protection Agency, Health Effects Research Laboratory (MD-71), Research Triangle Park, NC, 27711, USA

    Robert J. Kavlock (Director) (Director)

  3. Institut für Anatomie, Freie Universität Berlin, Königin-Luise-Strasse 15, W-1000, Berlin 33, Germany

    Hans-Joachim Merker

  4. Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Garystrasse 5, W-1000, Berlin 33, Germany

    Jane Klein

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© 1992 Springer-Verlag Berlin Heidelberg

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Nau, H. (1992). Pharmacokinetics and Drug Metabolism in the Design and Interpretation of Developmental Toxicity Studies. In: Neubert, D., Kavlock, R.J., Merker, HJ., Klein, J. (eds) Risk Assessment of Prenatally-Induced Adverse Health Effects. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-77753-0_23

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  • DOI: https://doi.org/10.1007/978-3-642-77753-0_23

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-77755-4

  • Online ISBN: 978-3-642-77753-0

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