Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate.
OBJECTIVE
Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina.


METHODS
Mid-gestational (day 75 +/- 13, n= 7) and late-gestational (day 150 +/- 10, n= 5) age macaques were imaged after administration of a prototypic P-gp substrate, (11)C-verapamil (13.7-75.4 MBq.kg(-1)), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg.kg(-1).h(-1)). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0-9 min) under the (11)C-radioactivity concentration-time curve in the tissue (AUC(tissue)) to that in the maternal plasma (AUC(plasma)).


RESULTS
The CsA-induced change in AUC(fetal liver)/AUC(maternal)(plasma) of (11)C-radioactivity significantly increased from mid- (35 +/- 25%) to late gestation (125 +/- 66%). Likewise, the CsA-induced change in AUC(maternal brain)/AUC(plasma) increased from mid- (172 +/- 80%) to late gestation (337 +/- 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating (11)C-verapamil metabolites were significantly affected by gestational age.


CONCLUSIONS
P-gp activity at the blood-brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy.
Chung
F S
FS
Department of Pharmaceutics, University of Washington, Seattle, Washington 98195, USA.
Eyal
S
S
Muzi
M
M
Link
J M
JM
Mankoff
D A
DA
Kaddoumi
A
A
O'Sullivan
F
F
Hsiao
P
P
Unadkat
J D
JD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D005865:Gestational Age; D008254:Macaca nemestrina; D008431:Maternal-Fetal Exchange; D009928:Organ Specificity; D010920:Placenta / Q000000981:diagnostic imaging / Q000378:metabolism; D049268:Positron-Emission Tomography; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014700:Verapamil / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019275:Radiopharmaceuticals; D016572:Cyclosporine; D014700:Verapamil