Pharmacokinetic profile and placental transfer of a single intravenous injection of [(14)C]chlorpyrifos in pregnant rats.

The pharmacokinetics and placental transfer of a single intravenous dose of 5.0 mg/kg (10 micro Ci/kg) ring-labeled [(14)C]chlorpyrifos were investigated in pregnant Sprague-Dawley rats at 11-13 days of gestation. Three rats were killed at 5, 15 or 30 min, or 1, 2, 4, 8, 12, 18, 24, 36, 48, 72 or 96 h after dosing. Radioactivity and 3,5,6-trichloropyridinol (TCP) were detected in all tissues 5 min after dosing. Chlorpyrifos was only found in maternal plasma and liver. Peak maternal plasma concentration of radioactivity ( micro g chlorpyrifos equivalents/ml) was 157 at 5 min, compared with 1.9 for fetal plasma at 15 min. The maximum concentrations of radioactivity ( micro g chlorpyrifos equivalents/g), detected in most tissues within 12 h of dosing, were, in descending order: liver (30), brain (29), placenta (21), and fetus (2). All peaks occurred at 5 min except for fetus and fetal plasma, which were at 15 min. TCP was detected by HPLC as the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 12.4 micro g/ml, and for the following tissues was: liver 4.3 ng/g fresh tissue, fetus 4 ng/g, placenta 2.97 ng/g, brain 1.68 ng/g, and fetal plasma 0.52 ng/g. All TCP peaks occurred at 5 min except for fetus at 30 min and fetal plasma at 15 min. Parent chlorpyrifos was detected in maternal plasma and liver at maximum concentrations of 5.1 micro g/ml and 0.40 micro g/g, respectively, at 5 min. Chlorpyrifos was detectable in maternal plasma up to 36 h after dosing, and in liver up to 24 h after dosing. Pharmacokinetic analysis best described radioactivity, chlorpyrifos, and TCP as disappearing biexponentially from plasma and tissues. The terminal elimination half-lives of radioactivity, chlorpyrifos and TCP from maternal plasma were 16, 18, and 16 h, respectively. The results indicate that (1). chlorpyrifos undergoes a rapid metabolism to its major metabolites (TCP); (2). chlorpyrifos and its metabolites are distributed to all maternal and fetal tissues and plasma; and (3). the elimination of chlorpyrifos and TCP is slow, with redistribution from lipid stores a likely determinant of elimination rates.

Robustness of MetaNet graph models: predicting control of urea production in humans.

Urea production in human liver was described by a MetaNet graph, a flowchart-like representation of metabolic pathways that includes parameters for the kinetic constants of the constituent enzymes. Formal operations on the graph facilitate the identification of ligand-binding equilibria that participate in feedback regulation in the network of biochemical reactions. The state of the biochemical network is specified by the concentrations of the intermediates. At any particular time, the influence of an identified locus of regulation is proportional to the respective fractional saturation of the corresponding binding site. Enzymes that make or consume the feedback chemicals share in the control of the strength of the feedback signal in proportion to their fractional saturation. This model predicts control of urea production by the processes that deliver amino groups to the urea cycle enzymes more than by the cycle enzymes themselves. Mitochondrial membrane transport processes are important for transmission of information through the network, but irreversible enzymes and processes far from equilibrium control the strength of the feedback signal. Systematic variation of the parameter values by amounts comparable to the expected variability of their measured values indicated a high probability of invariance in the identities of the predicted control points. The properties of the model are consistent with those of error-tolerant scale-free networks. These results demonstrate the robustness of a MetaNet model's predictions with respect to uncertainties in the values of its parameters.