A COMPUTER-MODEL AND PROGRAM FOR XENOBIOTIC DISPOSITION DURING PREGNANCY

A physiologically based pharmacokinetic computer model and program hav e been developed that depict internal disposition of chemicals during pregnancy in the mother and embryo/fetus. The model is based on human physiology but has been extended to simulate laboratory animal data. T he model represents the distribution, metabolism, and elimination of t wo chemicals in both the maternal and embryo/feral systems; the progra m handles the two chemicals completely independently or interactively with the two chemicals sharing routes of metabolism and/or elimination . The FORTRAN program computes the concentration of the two chemicals in 26 organs/tissues in the pregnant mother and 15 organs/tissues in t he embryo/fetus using a 486DX4 or Pentium PC. Adjustments for embryo/f etal organ and tissue volumes as a function of developmental age are m ade utilizing the Gompertz growth equation for the developing embryo/f etus and allometric relationships for the developing organs. Various c hanges in the maternal compartments which could affect the distributio n of a xenobiotic during pregnancy are also included in the model. Inp ut files require estimates of binding coefficients, first- and/or seco nd-order metabolism constants, level of interaction between the two ch emicals, and dosing information. Different possible routes of administ ration are included (e.g., i.v., infusion: oral, dermal, and inhalatio n, as well as repeated doses or exposures). Regression analysis can be conducted on any combination of these various parameters to fit actua l data. Output concentration-time curves are available simultaneously from all 82 differential equations. An illustrative example compares o bserved data with simulations for imipramine and its demethylated meta bolite, desipramine, in both the maternal rat and her fetuses. Methyl mercury data for the non-pregnant and pregnant rat also are compared w ith human data. Based on parameters determined from analysis of rat da ta, the model is readjusted for human physiology and predicts human ma ternal and fetal tissue concentrations as a function of time. (C) 1997 Elsevier Science Ireland Ltd.