Placenta kinetic studies

A16. Anagnostopoulos, C., and Matsudaira, H., Purification and kinetic studies of the alkaline phosphatase of human placenta. Proc. Intern. Symp. Enzyme Chtm., Tokyo Kyoto, 1957 (K. Ichihara, ed.), p. 166. Manizen, Tokyo, 1958. 

Quantification of PLP and PL as semicarbazone derivatives were also utilized for the analysis of PL kinase (EC 2.7.1.35), PM (PN) 5 -phosphate oxidase (EC 1.4.3.5) and PLP phosphatase activities (Fig. 8) in various tissues including erythrocytes (123), human placenta (124) and lymphocytes (Fig. 7). The detection of semicarbazone derivatives of both PLP and PL is very sensitive and the method is suitable for enzyme-kinetic studies (125). 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

This information is provided in the ICH-Guideline S3B Pharmacokinetics Guidance for repeated dose distribution studies (CPMP/ICH/395/95) . Other relevant kinetic questions are the investigations of the potential of compounds to penetrate the barriers of placenta, blood-brain or excretion into milk. 

A comparative study of the properties of human and rat 3-D-2-acetamido-2-deoxyhexosidases has been reported. There are four j3-D-2-acetamido-2-deoxy-hexosidases isoenzymes in rat serum one is thermostable and the remaining three are thermolabile. Human serum contains three isoenzymes two are thermostable and one is thermolabile. In general, the /3-D-2-acetamido-2-deoxy-hexosidases isoenzymes in rat serum are more thermolabile than those in human serum. In contrast, the kinetic properties of the j8-D-2-acetamido-2-deoxyhexo-sidase isoenzymes in serum from the two species are similar. Rat liver and human placenta contain two 3-D-2-acetamido-2-deoxyhexosidase isoenzymes, one of which is thermolabile and the other thermostable. These tissue isoenzymes from the two species have similar physical and kinetic properties. 

Estradiol-17j3-dehydrogenase from placenta is the only enzyme of which the kinetics have been studied. Since dehydrogenases are probably localized in the soluble fraction of cells, little difficulty should be encountered in their further study. 

The enzyme preparation used for these studies was purified approximately 40 fold from human placenta and assayed as previously described (Holmes, et al., 1973). In the absence of purine ribonucleotides human amidotransferase exhibits Michaelis-Menten kinetics for the substrate PP-ribose-P. However, the inclusion of purine ribonucleotides in the assay system results in a qualitative change in the kinetics from a hyperbolic to a sigmoidal function. The result is a marked inhibition of amidotransferase by purine ribonucleotides at physiological concentrations of PP-ribose-P. On the other hand the inhibition produced by purine ribonucleotides... 

---