Biotransformation of drugs and other xenobiotics during postnatal development

Klinger, W

doi:10.1016/0163-7258(82)90007-9

Cited by 53 publications

(1 citation statement)

References 405 publications

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“…This isoform is the homologue of human cytochrome P450 3A4 (Durr et al 2000), which is the main enzyme involved in the metabolism of toxic substances that are also substrates of P-glycoprotein, MRP1 and MRP2 (Guengerich 1999). The perinatal kidney is also incompletely developed, and drug transporters undergo important changes in activity during this period (Klinger 1982). The transcript was also detectable in the kidney and intestine, but in these two tissues it was not possible to demonstrate any regulation.…”

Section: Discussionmentioning

confidence: 98%

Physiological regulation of P‐glycoprotein, MRP1, MRP2 and cytochrome P450 3A2 during rat ontogeny

Rosati

Maniori

Decorti³

et al. 2003

Dev Growth Differ

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P-glycoprotein and the multidrug resistance-related proteins MRP1 and MRP2 belong to the ATP binding cassette family of proteins and transport a wide range of substrates. These proteins are also involved in metabolic and excretory processes of xenobiotics. The rat genes mdr1a and mdr1b code for P-glycoproteins, while mrp1 and mrp2 genes code for MRP1 and MRP2 proteins, respectively. In this study, the physiological modulation of the level of transcript for these genes during rat ontogeny in the liver, kidney, lung, brain and heart was analyzed by reverse transcription-polymerase chain reaction. An increasing level of transcript during ontogeny was demonstrated for mdr1a and mdr1b in all tissues considered, as well as for mrp2, which was detected only in the liver and kidney. In contrast, mrp1 transcript, present in all tissues, did not show any modulation. The maximum level of expression was reached in adult animals and a significant decrease was demonstrated in aging rats. Western blot analysis with C219 and M2III-6 monoclonal antibodies confirmed this different pattern of expression during ontogeny in the liver. The physiological regulation of cytochrome P450 3A2 was also considered: in the rat liver, an increase in the level of transcript during ontogeny, with a maximum in 60-day-old rats and a decrease in 8-month-old rats, was evident.

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Section: Discussionmentioning

confidence: 98%

Physiological regulation of P‐glycoprotein, MRP1, MRP2 and cytochrome P450 3A2 during rat ontogeny

Rosati

Maniori

Decorti³

et al. 2003

Dev Growth Differ

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Antidiarrheal specificity and safety of the n‐oxide of loperamide (R 58 425) in rats

Niemegeers

Awouters

et al. 1986

Drug Development Research

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Neimegeers, C.J.E., F. Awouters, F.M. Lenaerts, K.S.K. Artois, and J. Vermeire: Antidiarrheal specificity and safety of the N-oxide of loperamide (R 58 425) in rats. Drug Dev. Res. 8:279-286, 1986.The pharmacological and toxicological effects of loperamide and the N-oxide of loperamide were studied in adult and 19-day-old rats and in I-day-old pups. In adult rats both orally administered compounds were equipotent and specific antidiarrheals, but the N-oxide was slightly less toxic. In these rats, i.v. injected N-oxide, in contrast to loperamide, did not induce opiate-like central effects and its intestinal activity developed more gradually. In 19-day-old rats high oral doses of both compounds induced opiate-like behavioral effects, but the i.v. injected N-oxide was again virtually devoid of these effects and proved 5 times less toxic than i.v. loperamide. The orally administered compounds in 1-day-old pups induced lethality at doses slightly higher than the i.v. lethal doses of loperamide in 19-day-old and adult rats. The results are in agreement with rapid and efficient conversion of the N-oxide to loperamide in intestine and in liver, and a much slower and pharmacologically hardly detectable conversion of circulating N-oxide. The visceral barriers, which limit access of the orally administered compounds to the systemic circulation, appear fully developed in 19-day-old rats; the blood-brain barrier at this age is still more permeable than in adult rats. The more gradual development of antidiarrheal activity and the reduced risk of acute systemic intoxication are the major pharmacological differences between orally administered N-oxide and loperamide.

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Influence of metyrapone and phenobarbital on sodium dichromate nephrotoxicity in developing rats

Appenroth

Gambaryan

Friese³

et al. 1990

J of Applied Toxicology

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After the administration of equal doses of sodium dichromate, chromium concentrations in the kidney were lower in young than in adult rats. To test the age-dependent sensitivity to the nephrotoxicity of dichromate, young and adult rats were given doses to achieve identical chromium concentrations in the kidney. At equal renal concentrations, young rats had less functional and morphological damage than adult rats. As phenobarbital treatment in young rats enhanced the symptoms of nephrotoxicity and metyrapone treatment in adult rats decreased the symptoms of nephrotoxicity, age-dependent differences in chromate nephrotoxicity may be linked to an increase in the enzymatic reduction of Cr(VI) with age.

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Biotransformation of drugs and other xenobiotics during postnatal development

Cited by 53 publications

References 405 publications

Physiological regulation of P‐glycoprotein, MRP1, MRP2 and cytochrome P450 3A2 during rat ontogeny

Physiological regulation of P‐glycoprotein, MRP1, MRP2 and cytochrome P450 3A2 during rat ontogeny

Antidiarrheal specificity and safety of the n‐oxide of loperamide (R 58 425) in rats

Influence of metyrapone and phenobarbital on sodium dichromate nephrotoxicity in developing rats

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