Placental transfer and fetal metabolism of zidovudine in the baboon

Marianne Garland, Hazel H. Szeto, Salha S. Daniel, Pamela J. Tropper, Michael M. Myers, Raymond I. Stark

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Zidovudine (azidothymidine, AZT) is used in pregnancy to reduce mother to infant transmission of HIV. Understanding the disposition of AZT in the fetus is necessary to optimize therapeutic regimens directed toward the fetus. Recent studies in primates found similar steady-state levels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to those in the mother, raising the question of whether the metabolite was of fetal or maternal origin. The objective of this study was to determine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compartment model at steady state. Steady- state concentrations were obtained after paired maternal and fetal infusions of AZT in chronically catheterized pregnant baboons. During maternal infusion, the mean (±SE) fetal to maternal ratio of AZT was < 1 (0.84 ± 0.06, p < 0.02), suggesting clearance of AZT in the fetus. Mean total maternal clearance of AZT was 725 ± 49 mL/min and placental clearance was 36 ± 4 mL/min, or ~5% of maternal clearance. Fetal clearance of AZT was estimated at ~15% of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, but does not preclude the fetus from actively contributing to the metabolite in the fetal circulation. During infusion of AZT to the fetus, the concentration of AZT- glu in the ferns was 7.0 ± 0.8 times that in the mother. This is compelling evidence that glucuronide can be formed in the fetal compartment. Thus, fetal metabolism has an impact on the concentration of both AZT and AZT-glu in the fetal circulation.

Original languageEnglish (US)
Pages (from-to)47-53
Number of pages7
JournalPediatric Research
Volume44
Issue number1
StatePublished - Jul 1998
Externally publishedYes

Fingerprint

Zidovudine
Papio
Mothers
Fetus
Glucuronides
Ferns
Primates

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Garland, M., Szeto, H. H., Daniel, S. S., Tropper, P. J., Myers, M. M., & Stark, R. I. (1998). Placental transfer and fetal metabolism of zidovudine in the baboon. Pediatric Research, 44(1), 47-53.

Placental transfer and fetal metabolism of zidovudine in the baboon. / Garland, Marianne; Szeto, Hazel H.; Daniel, Salha S.; Tropper, Pamela J.; Myers, Michael M.; Stark, Raymond I.

In: Pediatric Research, Vol. 44, No. 1, 07.1998, p. 47-53.

Research output: Contribution to journalArticle

Garland, M, Szeto, HH, Daniel, SS, Tropper, PJ, Myers, MM & Stark, RI 1998, 'Placental transfer and fetal metabolism of zidovudine in the baboon', Pediatric Research, vol. 44, no. 1, pp. 47-53.
Garland M, Szeto HH, Daniel SS, Tropper PJ, Myers MM, Stark RI. Placental transfer and fetal metabolism of zidovudine in the baboon. Pediatric Research. 1998 Jul;44(1):47-53.
Garland, Marianne ; Szeto, Hazel H. ; Daniel, Salha S. ; Tropper, Pamela J. ; Myers, Michael M. ; Stark, Raymond I. / Placental transfer and fetal metabolism of zidovudine in the baboon. In: Pediatric Research. 1998 ; Vol. 44, No. 1. pp. 47-53.
@article{704beb4908054ab5bb2d5369948aa716,
title = "Placental transfer and fetal metabolism of zidovudine in the baboon",
abstract = "Zidovudine (azidothymidine, AZT) is used in pregnancy to reduce mother to infant transmission of HIV. Understanding the disposition of AZT in the fetus is necessary to optimize therapeutic regimens directed toward the fetus. Recent studies in primates found similar steady-state levels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to those in the mother, raising the question of whether the metabolite was of fetal or maternal origin. The objective of this study was to determine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compartment model at steady state. Steady- state concentrations were obtained after paired maternal and fetal infusions of AZT in chronically catheterized pregnant baboons. During maternal infusion, the mean (±SE) fetal to maternal ratio of AZT was < 1 (0.84 ± 0.06, p < 0.02), suggesting clearance of AZT in the fetus. Mean total maternal clearance of AZT was 725 ± 49 mL/min and placental clearance was 36 ± 4 mL/min, or ~5{\%} of maternal clearance. Fetal clearance of AZT was estimated at ~15{\%} of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, but does not preclude the fetus from actively contributing to the metabolite in the fetal circulation. During infusion of AZT to the fetus, the concentration of AZT- glu in the ferns was 7.0 ± 0.8 times that in the mother. This is compelling evidence that glucuronide can be formed in the fetal compartment. Thus, fetal metabolism has an impact on the concentration of both AZT and AZT-glu in the fetal circulation.",
author = "Marianne Garland and Szeto, {Hazel H.} and Daniel, {Salha S.} and Tropper, {Pamela J.} and Myers, {Michael M.} and Stark, {Raymond I.}",
year = "1998",
month = "7",
language = "English (US)",
volume = "44",
pages = "47--53",
journal = "Pediatric Research",
issn = "0031-3998",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Placental transfer and fetal metabolism of zidovudine in the baboon

AU - Garland, Marianne

AU - Szeto, Hazel H.

AU - Daniel, Salha S.

AU - Tropper, Pamela J.

AU - Myers, Michael M.

AU - Stark, Raymond I.

PY - 1998/7

Y1 - 1998/7

N2 - Zidovudine (azidothymidine, AZT) is used in pregnancy to reduce mother to infant transmission of HIV. Understanding the disposition of AZT in the fetus is necessary to optimize therapeutic regimens directed toward the fetus. Recent studies in primates found similar steady-state levels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to those in the mother, raising the question of whether the metabolite was of fetal or maternal origin. The objective of this study was to determine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compartment model at steady state. Steady- state concentrations were obtained after paired maternal and fetal infusions of AZT in chronically catheterized pregnant baboons. During maternal infusion, the mean (±SE) fetal to maternal ratio of AZT was < 1 (0.84 ± 0.06, p < 0.02), suggesting clearance of AZT in the fetus. Mean total maternal clearance of AZT was 725 ± 49 mL/min and placental clearance was 36 ± 4 mL/min, or ~5% of maternal clearance. Fetal clearance of AZT was estimated at ~15% of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, but does not preclude the fetus from actively contributing to the metabolite in the fetal circulation. During infusion of AZT to the fetus, the concentration of AZT- glu in the ferns was 7.0 ± 0.8 times that in the mother. This is compelling evidence that glucuronide can be formed in the fetal compartment. Thus, fetal metabolism has an impact on the concentration of both AZT and AZT-glu in the fetal circulation.

AB - Zidovudine (azidothymidine, AZT) is used in pregnancy to reduce mother to infant transmission of HIV. Understanding the disposition of AZT in the fetus is necessary to optimize therapeutic regimens directed toward the fetus. Recent studies in primates found similar steady-state levels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to those in the mother, raising the question of whether the metabolite was of fetal or maternal origin. The objective of this study was to determine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compartment model at steady state. Steady- state concentrations were obtained after paired maternal and fetal infusions of AZT in chronically catheterized pregnant baboons. During maternal infusion, the mean (±SE) fetal to maternal ratio of AZT was < 1 (0.84 ± 0.06, p < 0.02), suggesting clearance of AZT in the fetus. Mean total maternal clearance of AZT was 725 ± 49 mL/min and placental clearance was 36 ± 4 mL/min, or ~5% of maternal clearance. Fetal clearance of AZT was estimated at ~15% of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, but does not preclude the fetus from actively contributing to the metabolite in the fetal circulation. During infusion of AZT to the fetus, the concentration of AZT- glu in the ferns was 7.0 ± 0.8 times that in the mother. This is compelling evidence that glucuronide can be formed in the fetal compartment. Thus, fetal metabolism has an impact on the concentration of both AZT and AZT-glu in the fetal circulation.

UR - http://www.scopus.com/inward/record.url?scp=0031866433&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031866433&partnerID=8YFLogxK

M3 - Article

C2 - 9667370

AN - SCOPUS:0031866433

VL - 44

SP - 47

EP - 53

JO - Pediatric Research

JF - Pediatric Research

SN - 0031-3998

IS - 1

ER -