Comparative Teratology and Transplacental Pharmacokinetics of All-trans-Retinoic Acid, 13-cis-Retinoic Acid, and Retinyl Palmitate Following Daily Administrations in Rats

Collins, Michael D.; Tzimas, Georg; Hummler, Hans; Bürgin, Heinrich; Nau, Heinz

doi:10.1006/taap.1994.1147

Cited by 75 publications

(34 citation statements)

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“…The results are in agreement with previous observations of decreased plasma retinol concentration in the rat after treatment with 13cisRA (Berni et al, 1993;Collins et al, 1994) and with other retinoids with modifications in the area of the retinol hydroxyl end group, such as all-transRA and fenretinide (4HPR) (Bemi et al, 1993). In rats, although after administration of equimolar doses 13cisRA was slightly less potent than the other retinoids, it caused a remarkable and dose-dependent reduction in plasma retinol concentrations (Bemi et al, 1993).…”

Section: Maxsupporting

confidence: 93%

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Pharmacokinetics and effects on plasma retinol concentrations of 13-cis-retinoic acid in melanoma patients

Formelli

Cavadini²,

Mascheroni³

et al. 1997

Br J Cancer

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Summary The pharmacokinetics of 1 3-cis-retinoic acid (1 3cisRA) and its effects on retinol plasma levels were investigated after the first and the last doses in melanoma patients, who participated in a study run to assess tolerance over a long period of a treatment schedule of 1 3cisRA associated with recombinant interferon cu2a . Melanoma patients with regional node metastases after radical surgery were randomized to be treated for 3 months with rlFN-ca2a, 3 x 106 IU s.c. every other day, associated with oral 13cisRA at doses of 20 mg day-' (five patients) or 40 mg every other day (seven patients). Maximum 13cisRA blood concentrations usually occurred 4 h after drug administration, with average values of 406 and 633 ng ml-' (i.e. 1.3 and 2.1 gM) after the 20 and 40 mg dose respectively. The average halflife (t1,2) was approximately 30 h. The maximum concentration, the t,12 and the area under the concentration-time curves from 0 to 48 h (AUCOQ48) of 13cisRA did not change after multiple dosing, whereas the AUCO 48 of its major blood metabolite, 4-oxo-13-cis-retinoic acid, increased. Immediately after 1 3cisRA treatment, retinol plasma levels started to decline and they reached the lowest values (approximately 20% reduction) shortly after the time of maximum 13cisRA concentrations (i.e. 4-12 h after drug intake). Afterwards, values returned to baseline. The amount of retinol reduction in time was correlated with 1 3cisRA maximum concentrations.

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Section: Maxsupporting

confidence: 93%

“…Moreover, the effects of 13cisRA on endogenous vitamin A (retinol) were evaluated, as few and contrasting results have been reported (Goodman et al, 1982;Berni et al, 1993;Collins et al, 1994;Sass et al, 1995).…”

mentioning

confidence: 99%

Pharmacokinetics and effects on plasma retinol concentrations of 13-cis-retinoic acid in melanoma patients

Formelli

Cavadini²,

Mascheroni³

et al. 1997

Br J Cancer

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“…The same was true for retinyl palmitate, which has been found in chick limb buds but not in those of mice [24]. Comparable to the situation in mice [28] and rats [5], neither ddRA nor ddROH were detected in pig embryonic tissues. ddRA has previously been detected in the embryos of chickens [7,32] and rabbits [34].…”

Section: Discussionmentioning

confidence: 65%

Distribution of endogenous retinoids, retinoid binding proteins (RBP, CRABPI) and nuclear retinoid X receptor ? (RXR?) in the porcine embryo

et al. 2002

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-Retinoids are important signalling molecules in the development of limbs and in the determination of the anterior-posterior orientation of the embryo. The present study examined the content and distribution of retinoic acid, retinol and retinyl esters in porcine embryos during early gestation (gestation days 22-30) macroscopically and microscopically by its autofluorescence and by HPLC. Macroscopically, the yellowish-greenish autofluorescence characteristic of vitamin A was observed in tissues affected by morphogenesis, such as the limbs, in a spatial and temporal manner. Changes in the intensity of autofluorescence in the limbs paralleled changes in the concentration of retinoids in these structures. In the limbs and the body, retinol, retinyl palmitate, and all-trans-retinoic acid but neither the isomers of all-trans retinoic acid nor other retinoid metabolites were detected. In addition, the distribution of specific retinoid-binding proteins was investigated; these are involved in vitamin A transport, metabolism and signal transduction. Immunoreactive retinol-binding protein as well as cellular retinoic acid binding protein type I were only localised in the mesonephros, while the retinoid X receptor b was widely distributed in most of the tissues and organs of the embryo throughout the time period investigated. The combination of autofluorescence and HPLC analysis allowed for the first time to attribute the yellowish-greenish autofluorescence in specific regions of the embryo to vitamin A, and offers a method to study the local cellular distribution of retinol and/or retinyl esters as well as their concentrations in embryonic tissues. retinoid / vitamin A / binding protein / nuclear receptor / autofluorescence / embryo / pig Reprod. Nutr. Dev. 42 (2002) 285-294 285

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“…4). Despite the rather high intake of atRA during pregnancy by these dams, none of the resulting embryos exhibited any central nervous system (exencephaly and spina bifida) or craniofacial (protruding tongue and cleft palate) abnormalities that are characteristic of vitamin A toxicity (20,21). However, when skeletal development was studied, 54% of the embryos from the high RA-containing diet group exhibited an extranumerary (14th) lumbar rib.…”

Section: Resultsmentioning

confidence: 97%

“…Despite this fact, embryos from dams receiving 250 g of atRA per g of diet appear normal at E12.5 and show only minor differences from the RP (a source of ROL)-supplemented control group at E18.5. Previous studies of the teratogenic effects of the vitamin showed that 15 mg of atRA per kg per day administered as an oral bolus dose to pregnant rats between E7.5 and E15.5 results in exencephaly, protruding tongue, and cleft palate in 50-60% of fetuses, whereas 6 mg of atRA per kg per day given between E6.5 and E15.5 leads to the generation of only a supernumerary (14th) lumbar rib in about 42% of the fetuses (20). Fetuses from VAD dams fed 250 g of atRA per g of diet (16-18 mg of atRA per kg per day) exhibited no evidence of any central nervous system or craniofacial defects at E18.5; however, an additional lumbar (14th) rib was present in 54% of the fetuses examined at E18.5 (7 of 13).…”

Section: Discussionmentioning

confidence: 99%

Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all- trans- retinoic acid

White

Shankar

Highland

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

127

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Vitamin A is required for reproduction and normal embryonic development. We have determined that all-trans-retinoic acid (atRA) can support development of the mammalian embryo to parturition in vitamin A-deficient (VAD) rats. At embryonic day (E) 0.5, VAD dams were fed purified diets containing either 12 g of atRA per g of diet (230 g per rat per day) or 250 g of atRA per g of diet (4.5 mg per rat per day) or were fed the purified diet supplemented with a source of retinol (100 units of retinyl palmitate per day). An additional group was fed both 250 g of atRA per g of diet in combination with retinyl palmitate. Embryonic survival to E12.5 was similar for all groups. However, embryonic development in the group fed 12 g of atRA per g of diet was grossly abnormal. The most notable defects were in the region of the hindbrain, which included a loss of posterior cranial nerves (IX, X, XI, and XII) and postotic pharyngeal arches as well as the presence of ectopic otic vesicles and a swollen anterior cardinal vein. All embryonic abnormalities at E12.5 were prevented by feeding pharmacological amounts of atRA (250 g͞g diet) or by supplementation with retinyl palmitate. Embryos from VAD dams receiving 12 g of atRA per g of diet were resorbed by E18.5, whereas those in the group fed 250 g of atRA per g of diet survived to parturition but died shortly thereafter. Equivalent results were obtained by using commercial grade atRA or atRA that had been purified to eliminate any potential contamination by neutral retinoids, such as retinol. Thus, 250 g of atRA per g of diet fed to VAD dams (Ϸ4.5 mg per rat per day) can prevent the death of embryos at midgestation and prevents the early embryonic abnormalities that arise when VAD dams are fed insufficient amounts of atRA.

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Comparative Teratology and Transplacental Pharmacokinetics of All-trans-Retinoic Acid, 13-cis-Retinoic Acid, and Retinyl Palmitate Following Daily Administrations in Rats

Cited by 75 publications

References 0 publications

Pharmacokinetics and effects on plasma retinol concentrations of 13-cis-retinoic acid in melanoma patients

Pharmacokinetics and effects on plasma retinol concentrations of 13-cis-retinoic acid in melanoma patients

Distribution of endogenous retinoids, retinoid binding proteins (RBP, CRABPI) and nuclear retinoid X receptor ? (RXR?) in the porcine embryo

Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all- trans- retinoic acid

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