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Modeling cyclosporine A inhibition of the distribution of a P-glycoprotein PET ligand, 11C-verapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: impact of tissue blood flow and site of inhibition.

ABSTRACT: Through PET imaging, our laboratory has studied the dynamic biodistribution of (11)C-verapamil, a P-gp substrate, in the nonhuman primate Macaca nemestrina. To gain detailed insight into the kinetics of verapamil transport across the blood-brain barrier (BBB) and the blood-placental barrier (BPB), we analyzed these dynamic biodistribution data by compartmental modeling.Thirteen pregnant macaques (gestational age, 71-159 d; term, ?172 d) underwent PET imaging with (11)C-verapamil before and during infusion (6, 12, or 24 mg/kg/h) of cyclosporine A (CsA, a P-glycoprotein [P-gp] inhibitor). Dynamic (11)C-verapamil brain or fetal liver (reporter of placental P-gp function) activity was assessed by a 1- or 2-tissue-compartment model.The 1-tissue-compartment model best explained the observed brain and fetal liver distribution of (11)C-radioactivity. When P-gp was completely inhibited, the brain and fetal liver distribution clearance (K1) approximated tissue blood flow (Q); that is, extraction ratio (K1/Q) was approximately 1, indicating that in the absence of P-gp function, the distribution of (11)C-verapamil radioactivity into these compartments is limited by blood flow. The potency of CsA to inhibit P-gp was tissue-independent (maternal BBB half-maximal inhibitory concentration [IC50], 5.67 ± 1.07 ?M, vs. BPB IC50, 7.63 ± 3.16 ?M).We propose that on deliberate or inadvertent P-gp inhibition, the upper boundary of increase in human brain (or fetal) distribution of lipophilic drugs such as verapamil will be limited by tissue blood flow. This finding provides a means to predict the magnitude of P-gp-based drug interactions at the BBB and BPB when only the baseline distribution of the drug (i.e., in the absence of P-gp inhibition) across these barriers is available through PET. Our data suggest that P-gp-based drug interactions at the human BBB and BPB can be clinically significant, particularly for those P-gp substrate drugs for which P-gp plays a significant role in excluding the drug from these privileged compartments.

SUBMITTER: Ke AB

PROVIDER: S-EPMC4734747 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Modeling cyclosporine A inhibition of the distribution of a P-glycoprotein PET ligand, 11C-verapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: impact of tissue blood flow and site of inhibition.

Ke Alice Ban AB Eyal Sara S Chung Francisco S FS Link Jeanne M JM Mankoff David A DA Muzi Mark M Unadkat Jashvant D JD

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20130128 3

<h4>Unlabelled</h4>Through PET imaging, our laboratory has studied the dynamic biodistribution of (11)C-verapamil, a P-gp substrate, in the nonhuman primate Macaca nemestrina. To gain detailed insight into the kinetics of verapamil transport across the blood-brain barrier (BBB) and the blood-placental barrier (BPB), we analyzed these dynamic biodistribution data by compartmental modeling.<h4>Methods</h4>Thirteen pregnant macaques (gestational age, 71-159 d; term, ∼172 d) underwent PET imaging wi ...[more]

PMID: 23359659

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Project description: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.

Project description:Neuroreceptor imaging in the nonhuman primate (NHP) is valuable for translational research approaches in humans. However, most NHP studies are conducted under anesthesia, which affects the interpretability of receptor binding measures. The aims of this study were to develop awake NHP imaging with minimal head restraint and to compare in vivo binding of the ?-aminobutyric acid type A (GABAA)-benzodiazepine radiotracer (11)C-flumazenil under anesthetized and awake conditions. We hypothesized that (11)C-flumazenil binding potential (BPND) would be higher in isoflurane-anesthetized monkeys.The small animal PET scanner was fitted to a mechanical device that raised and tilted the scanner 45° while the awake NHP was tilted back 35° in a custom chair for optimal brain positioning, which required acclimation of the animals to the chair, touch-screen tasks, intravenous catheter insertion, and tilting. For PET studies, the bolus-plus-constant infusion method was used for (11)C-flumazenil administration. Two rhesus monkeys were scanned under the awake (n = 6 scans) and isoflurane-anesthetized (n = 4 scans) conditions. An infrared camera was used to track head motion during PET scans. Under the awake condition, emission and head motion-tracking data were acquired for 40-75 min after injection. Anesthetized monkeys were scanned for 90 min. Cortisol measurements were acquired during awake and anesthetized scans. Equilibrium analysis was used for both the anesthetized (n = 4) and the awake (n = 5) datasets to compute mean BPND images in NHP template space, using the pons as a reference region. The percentage change per minute in radioactivity concentration was calculated in high- and low-binding regions to assess the quality of equilibrium.The monkeys acclimated to procedures in the NHP chair necessary to perform awake PET imaging. Image quality was comparable between awake and anesthetized conditions. The relationship between awake and anesthetized values was BPND (awake) = 0.94 BPND (anesthetized) + 0.36 (r(2) = 0.95). Cortisol levels were significantly higher under the awake condition (P < 0.05).We successfully performed awake NHP imaging with minimal head restraint. There was close agreement in (11)C-flumazenil BPND values between awake and anesthetized conditions.

Project description:Little is known about the repertoire of nonhuman primate kidney genes expressed throughout development. The present work establishes an understanding of the primate renal transcriptome at different stages of fetal development and defines the framework of gene expression in the context of renal maturation, which provides a basis for identifying deviations in transcriptome expression resulting from suboptimal conditions during renal development. The baboon kidney transcriptome was characterized at 60 days gestation (DG), 90DG, 125DG, 160DG and adulthood (6-12 years) using human genome arrays to identify differential gene expression in the context of biological pathways and hierarchical clusters. Whole genome expression profiling showed 11,331 genes that were expressed during kidney development, 4,698 of which were differentially expressed among the developmental time points. Pathway analysis indicated activation of annotated pathways previously reported to be important to kidney development and pathways not reported as relevant to kidney development. QRT-PCR for genes central to these pathways validated expression profiles and revealed differences between males and females at specific times in gestation. Hierarchical clustering indicated that two clusters best fit the data, one containing genes that increased in expression from 60DG to adult and one that decreased. Cluster analysis also revealed gene splice variants with discordant expression profiles during development. For example, SMAD4, which is central to Wnt signaling, TGF-β signaling and cell cycle, showed up-regulation of the full-length splice variant during development and down-regulation of a shorter variant that is missing DNA binding and protein heterotrimerization domains suggesting decreased inhibition of cell proliferation, which may impact renal cell number and maturation. This study provides the first detailed genetic analysis of the developing primate kidney, and our findings of discordant expression of gene splice variants suggest that gene arrays likely provide a simplified view and demonstrate the need to study the fetal renal proteome.

Dataset Information

Modeling cyclosporine A inhibition of the distribution of a P-glycoprotein PET ligand, 11C-verapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: impact of tissue blood flow and site of inhibition.

Publications

Modeling cyclosporine A inhibition of the distribution of a P-glycoprotein PET ligand, 11C-verapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: impact of tissue blood flow and site of inhibition.

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