Developmental toxicity and pharmacokinetics of phenytoin in the rhesus macaque: An interspecies comparison

Hendrie, Tammy A.; Rowland, Jon M.; Binkerd, Pamela E.; Hendrickx, Andrew G.

doi:10.1016/0890-6238(90)90037-v

Cited by 7 publications

(5 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In rhesus macaque foetuses, no developmental abnormalities were seen when phenytoin was administered to the dam. Oral administration of 60 to 600 mg/kg phenytoin once a day from gestation day 21 to 50 resulted in dose-dependent maternal toxicity of the central nervous system and gastrointestinal tract and an increase in embryonic loss, but no teratogenic insult was found (Hendrie et al 1990). In an experimental study in the mouse, a positive correlation was found between increased plasma phenytoin levels from 20 to 60 mg/kg and frequency of congenital malformations.…”

Section: Discussionmentioning

confidence: 76%

“…Rowland et al (1990) found no decline in plasma concentration in the rat after a single oral dose of 1125 mg/kg during a 48 hr period on gestation day 8 and gestation day 17. Hendrie et al (1990) also found no decline in plasma concentration in the macaque after a single oral dose of 120 or 300 mg/kg during a 48 hr period on gestation day 21. Rowland et al (1990) suggests that due to saturation of the hepatic enzyme (CYP2C9) system necessary for the conversion of phenytoin to its major metabolite, conjugated p-HPPH, capacitylimited kinetics occur.…”

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat

Beekhuijzen

Verhoef

Klaassen

et al. 2000

Pharmacology & Toxicology

View full text Add to dashboard Cite

Abstract:The rat whole embryo culture was compared to an in vivo experiment with regard to embryotoxicity as well as exposure characteristics, using phenytoin as a model compound. Intra-embryonic concentrations and their embryotoxic effects were determined on gestation day 11 after in vitro administration of 50-150 mg/ml or in vivo gavage of 500-1500 mg/kg body-weight on gestation day 10. In addition, exposure kinetics were studied in vivo after a single oral dose on gestation day 10, and developmental defects on gestation day 21 were scored. The embryotoxic effects observed on gestation day 11 were more pronounced after in vitro exposure in comparison to in vivo exposure at similar intra-embryonic concentrations. Exposure of phenytoin on gestation day 10 in vitro via the culture medium resulted in general embryotoxicity on gestation day 11, whereas in vivo effects as determined on gestation day 11 were minimal. Plasma concentrations of phenytoin increased and plateaued around 35 mg/ml during the 48 hr monitoring period. Plasma concentration curves and pharmacokinetic parameters did not show remarkable differences between the dose groups, indicating that absorption is the limiting factor at the dose range used. Although the developmental effects were minimal as observed in vivo on gestation day 11, specific malformations (defects encompassing the urogenital, craniofacial and skeletal systems) were observed on gestation day 21. These findings show that with similar intra-embryonic concentrations of phenytoin the embryotoxicity in rat whole embryo culture was not comparable with the in vivo embryotoxicity as determined on gestation day 11. This discrepancy may at least partly be explained by differences in exposure characteristics.In embryotoxicity testing the in vitro test with closest resemblance to in vivo complexity available is the rodent whole embryo culture (New 1978). This system can be used to detect developmental effects of compounds on the isolated intact embryo during a developmentally critical 48 hr period (Schmid 1985; Bechter & Schö n 1988;Piersma et al. 1995Piersma et al. & 1996. For the interpretation of results of in vitro embryotoxicity testing, the nature of the effects observed and the lowest effective compound concentration are essential. As in vitro systems necessarily represent a small part of the living animal, extrapolation of these findings to the in vivo situation is not straightforward.The present study was carried out to compare an embryo culture experiment with an in vivo experiment in the rat with regard to exposure and effect characteristics, using phenytoin as a model compound. In man, phenytoin causes growth retardation, microcephaly, mental deficiency and craniofacial anomalies, known as the foetal hydantoin syndrome (Hanson & Smith 1975). Growth retardation and craniofacial defects have been produced in mice and rats in vivo (Lorente et al. 1981;Rowland et al. 1990; Finnell & Dansky 1991) and in embryo culture (Bruckner et al. 1983;Lindhout et al. 1987;Ozolins et al. 1995). T...

show abstract

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 91%

Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat

Beekhuijzen

Verhoef

Klaassen

et al. 2000

Pharmacology & Toxicology

View full text Add to dashboard Cite

show abstract

“…However, some human studies have cast doubt on the association between DPH exposure and teratologic risk (Livingston et al, ; Meyer, ; Goujard et al, ; Shepard and Lemire, ). Additionally, no obvious teratogenic effects were found in monkeys even at a maternotoxic and embryo‐lethal doses (Hendrie et al, ; Phillips and Lockard, ). These discrepancies among studies probably result from differences in the test systems used, experimental designs, or dosing regimens.…”

Section: Discussionmentioning

confidence: 99%

“…Hanson () reviewed the clinical effects and stated that not more than 5 to 10% of exposed infants develop hydantoin syndrome and that subtle changes can be found in 30%. In rhesus macaque fetuses, oral administration of 60 to 600 mg/kg DPH during the organogenetic period produced dose‐dependent maternal toxicity, but no teratogenic insult was found at any dose tested (Hendrie et al, ). Therefore, it is needed to obtain the reliable information regarding the teratogenic effects, correlation with maternal and developmental toxicity, and dose–response relationship of DPH.…”

Section: Introductionmentioning

confidence: 99%

Dose–Response Effects of Diphenylhydantoin on Pregnant Dams and Embryo‐Fetal Development in Rats

Kim

Lee

Baek

et al. 2012

Birth Defects Research Pt B

View full text Add to dashboard Cite

Despite the widespread use of diphenylhydantoin (DPH), there is a lack of reliable information on the teratogenic effects, correlation with maternal and developmental toxicity, and dose-response relationship of DPH. This study investigated the dose-response effects of DPH on pregnant dams and embryo-fetal development as well as the relationship between maternal and developmental toxicity. DPH was orally administered to pregnant rats from gestational days 6 through 15 at 0, 50, 150, and 300 mg/kg/day. At 300 mg/kg, maternal toxicity including increased clinical signs, suppressed body weight, decreased food intake, and increased weights of adrenal glands, liver, kidneys, and brain were observed in dams. Developmental toxicity, including a decrease in fetal and placental weights, increased incidence of morphological alterations, and a delay in fetal ossification delay also occurred. At 150 mg/kg, maternal toxicity manifested as an increased incidence of clinical signs, reduced body weight gain and food intake, and increased weights of adrenal glands and brain. Only minimal developmental toxicity, including decreased placental weight and an increased incidence of visceral and skeletal variations, was observed. No treatment-related maternal or developmental effects were observed at 50 mg/kg. These results show that DPH is minimally embryotoxic at a minimal maternotoxic dose (150 mg/kg/day) but is embryotoxic and teratogenic at an overt maternotoxic dose (300 mg/kg/day). Under these experimental conditions, the no-observed-adverse-effect level of DPH for pregnant dams and embryo-fetal development is considered to be 50 mg/kg/day. These data indicate that DPH is not a selective developmental toxicant in the rat.

show abstract

“…The pharmacokinetics of phenytoin are different in the rat, rabbit, dog, and human; however, neurotoxicity in all of these species is observed when plasma phenytoin concentrations exceed 30 4g/ml (8 (12) showed that nephrotoxicity in dogs after continuous administration of gentamicin and tobramycin by intravenous infusion is significantly higher than that after administration of the drug every 4 hr as intravenous bolus. Administration of 45 mg gentamicin/kg/day to dogs for 10 days reduced their glomerular filtration rate by 86% when the drug was infused continuously and only 29% when given every 4 hr.…”

Section: A Basic Assumptionmentioning

confidence: 99%

Toxicokinetics/Toxicodynamic Correlations: Goals, Methods, and Limitations

Batra¹

1995

Toxicol Pathol

View full text Add to dashboard Cite

Developmental toxicity and pharmacokinetics of phenytoin in the rhesus macaque: An interspecies comparison

Cited by 7 publications

References 32 publications

Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat

Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat

Dose–Response Effects of Diphenylhydantoin on Pregnant Dams and Embryo‐Fetal Development in Rats

Toxicokinetics/Toxicodynamic Correlations: Goals, Methods, and Limitations

Contact Info

Product

Resources

About