지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
커뮤니티
연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2013.3
- 수록면
- 53 - 60 (8page)
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초록· 키워드
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Studies on milk transfer of drugs in non-human primates (NHPs) are among the crucial components in the assessment of peri- and postnatal toxicity because of the similarity between NHPs and humans. To evaluate the milk transfer of valproic acid (VPA) in NHPs, the toxicokinetics of VPA, an antiepileptic drug, were studied in pregnant cynomolgus monkeys. VPA was administered once daily to pregnant cynomolgus monkeys at doses of 0, 30, 90, and 270 mg/kg by oral gavage from Day 100 of gestation (GD 100) to Day 31 of lactation (LD 31). Concentrations of VPA and its metabolite, 4-ene-VPA, in the maternal plasma on GD 100, GD 140, and LD 30, and concentrations of VPA and 4-ene-VPA in the offspring plasma and milk on LDs 30 and 31, respectively, were quantified using liquid chromatography tandem mass spectrometry (LC/MS/MS). After administration of a single oral dose of VPA to pregnant monkeys on GD 100, the concentrations of VPA and 4-ene-VPA were generally quantifiable in the plasma of all treatment groups up to 24 hr after administration, which showed that VPA was absorbed and that the monkeys were systemically exposed to VPA and 4-ene-VPA. After administration of multiple doses of VPA to the monkeys, VPA was detected in the pup’s plasma and in milk taken on LD 30 and LD 31, respectively, which showed that VPA was transferred via milk, and the pup was exposed to VPA. Further, the concentration of VPA in the milk increased with an increase in the dose. Extremely low concentrations of 4-ene VPA were detected in the milk and in the pup plasma. In conclusion, pregnant monkeys were exposed to VPA and 4-ene-VPA after oral administration of VPA at doses of 30, 90, and 270 mg/kg/day from GD 100 to LD 31. VPA was transferred via milk, and the VPA exposure to the pup increased with an increase in the dose of VPA. The metabolite, 4-ene VPA, was present in extremely low concentrations (< 0.5 μg/ml) in the milk and in the pup plasma. In this study, we established methods to confirm milk transfer in NHPs, such as mating and diagnosis of pregnancy by examining gestational sac with ultrasonography, collection of milk and pup plasma and determination of toxicokinetics, using cynomolgus monkeys.
목차
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
참고문헌 (25)
참고문헌 신청
Ornoy, A. / 2006 / Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reprod / Toxicol. 22:214~226
Rosenberg, G. / 2007 / The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? / Cell. Mol. Life Sci. 64:2090~2103
Wide, K. / 2004 / Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study / Acta Paediatr. 93:174~176
Alsdorf, R. / 2005 / Teratogenicity of sodium valproate / Expert Opin. Drug Saf. 4:345~353
Binkerd, P. E. / 1988 / Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats / Fundam. Appl. Toxicol. 11:485~493
Rosenberg, G. / 2007 / The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? / Cell. Mol. Life Sci. 64:2090~2103
Wide, K. / 2004 / Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study / Acta Paediatr. 93:174~176
Alsdorf, R. / 2005 / Teratogenicity of sodium valproate / Expert Opin. Drug Saf. 4:345~353
Binkerd, P. E. / 1988 / Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats / Fundam. Appl. Toxicol. 11:485~493
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UCI(KEPA) : I410-ECN-0101-2014-510-003159959