Unknown

Dataset Information

0

Simultaneous PET imaging of P-glycoprotein inhibition in multiple tissues in the pregnant nonhuman primate.


ABSTRACT: Studies in rodents indicate that the disruption of P-glycoprotein (P-gp) function increases drug distribution into the developing fetus and organs such as the brain. To simultaneously and serially evaluate the effect of P-gp activity and inhibition on the tissue distribution of drugs in a more representative animal model, we tested the feasibility of conducting whole-body PET of the pregnant nonhuman primate (Macaca nemestrina). We used (11)C-verapamil as the prototypic P-gp substrate and cyclosporine A (CsA) as the prototypic inhibitor.Four pregnant macaques (gestational age, 145-159 d; gestational term, 172 d) were imaged after the intravenous administration of (11)C-verapamil (30-72 MBq/kg) before and during intravenous infusion of CsA (12 or 24 mg/kg/h, n = 2 each). The content of verapamil and its metabolites in plasma samples was determined using a rapid solid-phase extraction method. The plasma and tissue time-radioactivity concentration curves of (11)C were integrated over 0-9 min after each verapamil injection. The tissue or arterial plasma area under the time-concentration curve (AUC(tissue)/AUC(plasma)) served as a measure of the tissue distribution of (11)C radioactivity. CsA effect on (11)C radioactivity distribution was interpreted as P-gp inhibition. The change in the fetal liver AUC ratio served as a reporter of placental P-gp inhibition.CsA effect on tissue distribution of (11)C radioactivity (AUC ratios) did not increase with the mean blood concentration of CsA, indicating a near-maximal P-gp inhibition. CsA increased maternal brain and fetal liver distribution of (11)C radioactivity by 276% +/- 88% (P < 0.05) and 122% +/- 75% (P < 0.05), respectively. Changes in other measured tissues were not statistically significant.These data demonstrate for the first time, to our knowledge, the feasibility of simultaneous, serial, noninvasive imaging of P-gp activity and inhibition in multiple maternal organs and the placenta in the nonhuman primate. Our findings, consistent with previous data in rodents, indicate that the activity of P-gp in the placenta and the blood-brain barrier is high and that the inhibition of P-gp facilitates drug distribution across these barriers.

SUBMITTER: Eyal S 

PROVIDER: S-EPMC2703489 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

Simultaneous PET imaging of P-glycoprotein inhibition in multiple tissues in the pregnant nonhuman primate.

Eyal Sara S   Chung Francisco S FS   Muzi Mark M   Link Jeanne M JM   Mankoff David A DA   Kaddoumi Amal A   O'Sullivan Finbarr F   Hebert Mary F MF   Unadkat Jashvant D JD  

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20090501 5


<h4>Unlabelled</h4>Studies in rodents indicate that the disruption of P-glycoprotein (P-gp) function increases drug distribution into the developing fetus and organs such as the brain. To simultaneously and serially evaluate the effect of P-gp activity and inhibition on the tissue distribution of drugs in a more representative animal model, we tested the feasibility of conducting whole-body PET of the pregnant nonhuman primate (Macaca nemestrina). We used (11)C-verapamil as the prototypic P-gp s  ...[more]

Similar Datasets

| S-EPMC4734747 | biostudies-literature
| S-EPMC5714271 | biostudies-literature
| S-EPMC6004556 | biostudies-literature
2016-09-12 | GSE84614 | GEO
| S-EPMC5365281 | biostudies-literature
| S-EPMC3857935 | biostudies-literature
| S-EPMC304106 | biostudies-other
| S-EPMC6217390 | biostudies-literature
| S-EPMC3170450 | biostudies-literature
| S-EPMC5218859 | biostudies-other