Species difference in pharmacokinetics and teratogenesis of retinol and its metabolites
Species difference in pharmacokinetics and teratogenesis of retinol and its metabolites
Ten healthy female volunteers were given 5 doses of retinol as palmitate; 50 & 150mg/kg retinol as an oral supplement, 50 & 150 mg as fried calf liver (50 and 150g) and 3, 9 or 30 mg by intra-muscular injection. Plasma concentrations of retinyl palmitate and retinol showed only small differences between supplements and liver. The peak plasma concentrations (Cmax) of all-trans-retinoic acid (all-trans-RA), the principal teratogenic metabolite of retinol, and the area under the concentration-time curve (AIC) were up to 20 times higher after supplements compared to the same dose as liver. Plasma concentrations of all-trans-4-oxo-retinoic acid (all-trans-4-oxo-RA), 13-cis-retinoic acid (13-cis-RA) and 13-cis-4-oxo-retinoic acid (13-cis-4-oxo-RA) showed smaller differences between supplements and liver. Based on the formation of all-trans-RA alone, liver and supplements are not of equivalent teratogenic potential.
A divided dose (3 x 16.66mg/kg) of all-trans-RA produced similar teratogenic effects to a single oral dose (50mg/kg): however the pharmacokinetic data revealed that the total AUC from the divided doses was equivalent to about 20mg/kg as a single dose which would produce only a minimal teratogenic effect. This study therefore demonstrated the possibility of an additional and important variable influencing the relationship between dose, kinetics and response for all-trans-RA.
Human liver, intestinal mucosa and placenta-trophoblast as well as rat liver and gut mucosa were capable of isomerizing all-trans and 13-cis-RA in vitro. The rate of formation of all-trans-RA from tissues incubated with 13-cis-RA was significantly greater than the formation of 13-cis-RA from all-trans-RA. The human liver was more effective than the intestinal mucosa in the formation of all-trans-RA. In contrast, the rat gut mucosa was more effective than the liver in the formation of all-trans-RA. This introduces the possibility of systemic isomerization of 13-cis-RA to the teratogenic metabolite all-trans-RA and also highlights the danger of extrapolating between species.
University of Southampton
Tembe, Estella Achick
f2228455-18f9-450b-9d8d-feff5dbe673c
1994
Tembe, Estella Achick
f2228455-18f9-450b-9d8d-feff5dbe673c
Tembe, Estella Achick
(1994)
Species difference in pharmacokinetics and teratogenesis of retinol and its metabolites.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Ten healthy female volunteers were given 5 doses of retinol as palmitate; 50 & 150mg/kg retinol as an oral supplement, 50 & 150 mg as fried calf liver (50 and 150g) and 3, 9 or 30 mg by intra-muscular injection. Plasma concentrations of retinyl palmitate and retinol showed only small differences between supplements and liver. The peak plasma concentrations (Cmax) of all-trans-retinoic acid (all-trans-RA), the principal teratogenic metabolite of retinol, and the area under the concentration-time curve (AIC) were up to 20 times higher after supplements compared to the same dose as liver. Plasma concentrations of all-trans-4-oxo-retinoic acid (all-trans-4-oxo-RA), 13-cis-retinoic acid (13-cis-RA) and 13-cis-4-oxo-retinoic acid (13-cis-4-oxo-RA) showed smaller differences between supplements and liver. Based on the formation of all-trans-RA alone, liver and supplements are not of equivalent teratogenic potential.
A divided dose (3 x 16.66mg/kg) of all-trans-RA produced similar teratogenic effects to a single oral dose (50mg/kg): however the pharmacokinetic data revealed that the total AUC from the divided doses was equivalent to about 20mg/kg as a single dose which would produce only a minimal teratogenic effect. This study therefore demonstrated the possibility of an additional and important variable influencing the relationship between dose, kinetics and response for all-trans-RA.
Human liver, intestinal mucosa and placenta-trophoblast as well as rat liver and gut mucosa were capable of isomerizing all-trans and 13-cis-RA in vitro. The rate of formation of all-trans-RA from tissues incubated with 13-cis-RA was significantly greater than the formation of 13-cis-RA from all-trans-RA. The human liver was more effective than the intestinal mucosa in the formation of all-trans-RA. In contrast, the rat gut mucosa was more effective than the liver in the formation of all-trans-RA. This introduces the possibility of systemic isomerization of 13-cis-RA to the teratogenic metabolite all-trans-RA and also highlights the danger of extrapolating between species.
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Published date: 1994
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Local EPrints ID: 462938
URI: http://eprints.soton.ac.uk/id/eprint/462938
PURE UUID: 1fb53692-c60c-49d3-8159-60d3974750f0
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Date deposited: 04 Jul 2022 20:28
Last modified: 23 Jul 2022 01:08
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Author:
Estella Achick Tembe
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