Abstract
It becomes increasingly clear that the dose is often an unsatisfactory correlate to the toxic effect produced by a drug or environmental agent. The effect in a particular target organ is strictly dependent on the concentration-time relationships of the drug and/or its active metabolite(s) in the target tissue, or, as in the case of “irreversible” pharmacokinetics, on reactive metabolites formed or specific binding phenomena (Monro, 1992). Thus, an effect is dependent on the chemical structure of the xenobiotic (intrinsic activity), the exposure of the target tissue, and the susceptibility or sensitivity toward a particular insult (pharmacogenetics) (Scheme 1). This general concept will be discussed here with
“the fundamental and analytical aspects of a problem are intimately interrelated; they are almost like the two sides of the same coin”
Pete Kolthoff
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References
Chodera, A., and Feller, K., 1978, Some aspects of pharmacokinetic and biotransformation differences in humans and mammal animals, Int. J. Clin.Pharmacol. 16:357–360.
Ehlers, K., Stürje, H., Merker, HJ., and Nau, H. 1992, Valproic acid-induced spina bifida: a mouse model, Teratology, 45:145–154.
Freireich, E.J., Gehan, E.A., Rail, D.P., Schmidt, L.H. and Skipper, H.E., 1966, Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man, Cancer Chemotherap. Recepts. 50:219–245.
Hamar, C, and Levy, G., 1980, Factors affecting the serum protein binding of salicylic acid in newborn infants and their mothers, Pediatr. Pharmacol. 1:31.
Hauck, R.S., and Nau, H., 1989, Asymmetric synthesis and enantioselective teratogenicity of 2-n-propyl-4-pentenoic acid (4-en-VPA), an active metabolite of the anticonvulsant drug, valproic acid, Toxicol. Lett. 49:41–48.
Hauck, R.S., Elmazar, M.M.A., Plum, C. and Nau, H., 1992, The enantioselective teratogenicity of 2-n-propyl-4-pentynoic acid (4-yn-VPA) is due to stereoselective instrinsic activity and not differences in pharmacokinetics, Toxicol. Lett. 60:145–153.
Hauck, R.S., Wegner, C., Blumtritt, P., Fuhrhop J.H. and 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.
Ings, R.M.J., 1990, Interspecies scaling and comparisons in drug development and toxicokinetics, Xenobiotica, 20,11:1201–1231.
Krauer, B., et al., 1986, Serum protein binding of diazepam and propranolol in the feto-maternal unit from early to late pregnancy, Br. J. Obstet. Gynaecol. 93:322.
Kuhnz, W., and Nau, H., 1983, Differences in in vitro binding of diazepam and demethyldiazepam to maternal and fetal plasma proteins at birth: Relation to free fatty acid concentrations and other parameters, Clin. Pharmacol. Ther. 34:220.
Lindhout, D. and Schmidt, D., 1986, In utero exposure to valproate and neural tube defects, Lancet, i:1392–1393.
Löfberg, B., Reiners, J., Spielmann, H., and 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 Ther. 15:45–51.
Luck, W., and Nau, H., 1984, Exposure of the fetus, neonate, and nursed infant to nicotine and cotinine from maternal smoking, New Engl. J. Med. 311:672.
Luck, W., and Nau, H., 1985, Nicotine and cotinine concentrations in serum and urine of infants exposed via passive smoking or milk from smoking mothers, J. Pediatr. 107:816–20.
Luck, W., and Nau, H., 1987, Nicotine and cotinine concentrations in the milk of smoking mothers: influence of cigarette consumption and diurnal variation, Eur. J. Pediatr. 146:21–6.
Luck, W., Nau, H., Hansen, R., and Steldinger, R., 1985, Extent of nicotine and continine transfer to the human fetus, placenta and amniotic fluid of smoking mothers, Dev. Pharmacol. Ther. 8:384–395.
Lutz, R.J., Dedrick, R.L., and Zaharko D., 1980, Physiological pharmacokinetics: an in vivo approach to membrane transport, Pharmac. Ther. 11:559–592.
Merker, HJ., Heger, W., Sames, K., Stürje, H. and Neubert, D., 1988, Embryotoxic effects of thalidomide derivatives in the non-human primate Callithrbc jacchus, I. Effects of 3-(l,3-dihydro-l-oxo-2H-isoindol-2-yl)-2,6- dioxopiperidine (EM 12) on skeletal development, Arch. Toxicol. 61:165–179.
Mirkin, B.L., and Singh, S., 1976, Placental transfer of pharmacologically active molecules, in: “Perinatal Pharmacology and Therapeutics,” B.L. Mirkin, ed., Academic Press, New York.
Monro, A., 1992, What is an appropriate measure of exposure when testing drugs for carcinogenicity in rodents?, Toxicol. Appl. Pharmacol. 112:171–181
Mordenti, J., 1986, Man versus beast: pharmacokinetic scaling in mammals, J. Pharma. Sci 75, 11:1028–1040.
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.
Nau, H., 1985b, Teratogenic valproic acid concentrations: infusion by implanted minipumps vs conventional injection regimen in the mouse, Toxicol. Appl. Pharmacol. 80:243–250.
Nau, H., 1986a, Species differences in pharmacokinetics and drug teratogenesis, Environ, Health Perspect. 70:113–129.
Nau, H., 1986b, 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, Fundam. Appl. Toxicol. 6:662–668.
Nau, H., 1990, Correlation of transplacental and maternal pharmacokinetics of retinoids during organogenesis with teratogenicity, Meth. Enzymol. 190:437–448.
Nau, H., 1991a, Pharmacokinetic considerations in the design and interpretation of developmental toxicity studies, “Symposium: Pharmacokinetics in Developmental Toxicity”, pp 219–221. SOCIETY OF TOXICOLOGY?
Nau, H., 1991b, Physiochemical and structural properties regulating placental drug transfer, in: “Fetal and Neonatal Physiology,” Vol. 1, R.A. Polin, and W.W. Fox, eds., Saunders, Philadelphia.
Nau, H., and Baß, R., 1981, Transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the mouse embryo and fetus, Toxicology. 20:299–308.
Nau, H., and 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.
Nau, H. and Scott, W.J., 1986, Weak acids may act as teratogens by accumulating in the basic milieu of the early mammalian embryo, Nature, 323:276–278.
Nau, H., Baß, R., and Neubert, D., 1986, Transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via placenta and milk, and postnatal toxicity in the mouse, Arch. Toxicol. 59:36–40.
Nau, H., Hauck, R.S., and Ehlers, K., 1991, Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms, Pharmacol. & Toxicol. 69:310–321.
Nau, H., Helge, H., and Luck, W., 1984, Valproic acid in 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.
Nau, H., Zierer, R., Spielmann, H., Neubert, D., and Gansau, G, 1981, A new model for embryotoxicity testing: teratogenicity and pharmacokinetics of valproic acid following constant-rate administration in the mouse using human therapeutic drug and metabolite concentrations, Life Sci. 29:2803–2814.
Neubert, D., and Chahoud, I., 1985, Significance of species and strain differences in pre- and perinatal toxicology, Acta Histochem. [Suppl.] 31:23–35.
Neubert, D., Heger, W., Merker, H.J., Sames, K., and Meister, R., 1988, Embryotoxic effects of thalidomide derivatives in the non-human primate Callithrix jacchus, II. Elucidation of the susceptible period and of the variability of embryonic states, Arch. Toxicol. 61:180–191.
Robert, E., 1988, Valproic acid as a human teratogen, Cong. Anom. 28 [Suppl.]: 71–80.
Schmahl, HJ., Heger, W., and Nau, H., 1989, The enantiomers of the teratogenic thalidomide analogue EM 12. Toxicol Lett. 45:23–33.
Schulte-Hobein, B., Schwartz-Bickenbach, D., Abt, S., Plum, C., and Nau, H., 1992, Cigarette smoke exposure and development of infants throughout the first year of life: influence of passive smoking and nursing on cotinine levels in breast milk and infant’s urine, Acta Paediatr. 81:550–557.
Scialli, A., 1992, “A Clinical Guide to Reproductive and Developmental Toxicology”, CRC Press, Boca Raton, Ann Arbor, London.
Smith, D.A., Humphrey, M.J., and Charuel, C, 1990, Design of toxicokinetic studies, Xenobiotica, 20, 11:1187–1199.
Sterz, H., Nothdurft, H., Lexa, P., and Ockenfels, H., 1987, Teratologic studies on the Himalayan rabbit: new aspects of thalidomide-induced teratogenesis, Arch. Toxicol. 60:376–381.
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Nau, H. (1993). Factors Determining the Exposure of the Embryo and Fetus: Species Variation of Teratogenesis and Placental Transfer of Xenobiotics. In: Travis, C.C. (eds) Use of Biomarkers in Assessing Health and Environmental Impacts of Chemical Pollutants. NATO ASI Series, vol 250. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-2052-2_14
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