Development of a Physiologically Based Pharmacokinetic Model to Describe the Disposition of Methanol in Pregnant Rats and Mice

Ward, Keith W.; Blumenthal, Gregory M.; Welsch, Frank; Pollack, Gary M.

doi:10.1006/taap.1997.8170

Cited by 33 publications

(13 citation statements)

References 32 publications

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“…More thorough studies calculate fetal and maternal elimination clearances and placental clearances using steadystate equations after maternal and fetal drug administration (6)(7). Maternal/fetal drug distribution also has been described in the literature by means of physiologically based pharmacokinetic modeling, which is a very thorough and laborious method of quantifying drug disposition (8)(9).…”

Section: Introductionmentioning

confidence: 99%

Area/Moment and Compartmental Modeling of Pharmacokinetics During Pregnancy: Applications to Maternal/Fetal Exposures to Corticosteroids in Sheep and Rats

Samtani

Schwab

Nathanielsz³

et al. 2004

Pharm Res

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Section: Introductionmentioning

confidence: 99%

Area/Moment and Compartmental Modeling of Pharmacokinetics During Pregnancy: Applications to Maternal/Fetal Exposures to Corticosteroids in Sheep and Rats

Samtani

Schwab

Nathanielsz³

et al. 2004

Pharm Res

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“…Several TK models developed for MeOH exposure have been published (Horton et al 1992;Perkins et al 1995;Damian and Raabe 1996;Ward et al 1997). These are mainly rodent-models and do not deal with the question of the potential use of MeOH itself or of FA as biomarkers, or with the role and formation of FA after low-level human MeOH exposure.…”

Section: Resultsmentioning

confidence: 99%

Toxicokinetic modelling of methyl formate exposure and implications for biological monitoring

Nihlén

Droz

2000

International Archives of Occupational and Environmental Health

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A toxicokinetic (TK) model was developed to describe the inhalation exposure in humans to methyl formate (MF), a catalyst used in foundries, and to discuss biological monitoring. The TK model consisted of four compartments: MF, the metabolites--methanol (MeOH) and formic acid (FA)--and, in addition, a urinary compartment describing the saturable reabsorption of FA. Levels of MeOH and FA in urine, from an experimental study (100 ppm MF, 8 h at rest), validated the present model. The TK model describes well the general behaviour of MeOH and FA in urine after MF exposure. A nonlinear and a linear relationship respectively, was predicted between MF exposure and FA or MeOH excretion in urine, and this has previously been seen after occupational MF exposure. The present model has been modified to simulate MeOH exposure as well. Generally low exposures (concentration or exercise) produce only marginal increases in FA urinary excretions, but when exposure is elevated, urinary FA excretion increases because of saturation in the mechanism of reabsorption. Using FA urinary excretion as the critical indicator, because of its link to health effects, an occupational exposure limit value for MF of no greater than 50 ppm should be selected (based on predictions with the TK model). MeOH in urine can be considered as a biomarker for MF at low exposure, because of lower background values and of a linear relationship with exposure. At higher exposures, however, FA could be used as a biomarker as it becomes progressively more sensitive. But the use of biological monitoring for MF is difficult because of individual variations in background values. Under the present state of knowledge both FA and MeOH should be used to estimate only group exposures, rather than individual exposures.

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“…Of the PBPK models in pregnant rats for volatile chemicals to date (Fisher et al, 1989;Gargas et al, 2000;Hays et al, 2000;Terry et al, 1995;Ward et al, 1997), the scaled ventilation for nonpregnant rats was used for the pregnant rats. However, as measured in the current study, the scaled ventilation in the pregnant rats at GD 21 is approximately 16% lower compared with nonpregnant rats.…”

Section: Discussionmentioning

confidence: 99%

“…Corley et al (2003) published a literature review of models for the disposition of xenobiotics during pregnancy. PBPK models for inhaled xenobiotics including trichloroethylene, methanol, and 2-methoxyethanol (Fisher et al, 1989;Gargas et al, 2000;Hays et al, 2000;Terry et al, 1995;Ward et al, 1997) have been developed for pregnant animals. In general, these models assumed that the alveolar ventilation scaled to body weight in pregnant and nonpregnant rats were equivalent.…”

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confidence: 99%

Respiration in Sprague-Dawley Rats During Pregnancy

Leavens

Parkinson

James

et al. 2006

Inhalation Toxicology

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Minute ventilation and tidal volume increase in humans during pregnancy. Little data exists, however, on the respiration in pregnant rats, despite their widespread use as an animal model. Since respiration will affect the pharmacokinetics of volatile compounds and ultimately the dose to the fetus, we conducted a study to evaluate respiration in rats during pregnancy. Whole-body plethysmography was used to measure the breathing frequency and tidal volume approximately every other day from gestation day (GD) 1 to 21 in 16 timed pregnant and 16 nonpregnant, female, Sprague-Dawley rats. Minute ventilation was calculated as a product of the breathing frequency and tidal volume, and the body weight of each rat was used to determine the scaled ventilation. Multivariate analysis of variance methods for a repeated-measures design were used to analyze the respiratory data. Breathing frequency was not affected by pregnancy; however, tidal volume was somewhat greater in pregnant versus nonpregnant rats. The increase in tidal volume resulted in significantly increased minute ventilation in pregnant rats compared to nonpregnant rats during the latter period of gestation. Due to the increased body weight of the pregnant rats, the scaled ventilation at the end of gestation was significantly lower in pregnant rats compared to nonpregnant rats. This study provides important reference values that can be used in pharmacokinetic models during pregnancy.

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Development of a Physiologically Based Pharmacokinetic Model to Describe the Disposition of Methanol in Pregnant Rats and Mice

Cited by 33 publications

References 32 publications

Area/Moment and Compartmental Modeling of Pharmacokinetics During Pregnancy: Applications to Maternal/Fetal Exposures to Corticosteroids in Sheep and Rats

Area/Moment and Compartmental Modeling of Pharmacokinetics During Pregnancy: Applications to Maternal/Fetal Exposures to Corticosteroids in Sheep and Rats

Toxicokinetic modelling of methyl formate exposure and implications for biological monitoring

Respiration in Sprague-Dawley Rats During Pregnancy

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