Maternal-fetal in vivo imaging: a combined PET and MRI study

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2005

Cocaine use during pregnancy has been shown to be deleterious to the infant. This may reflect reduction of flow to placenta or effects on the fetal brain. Methods to assess pharmacokinetics of drugs of abuse in vivo would be useful to investigate the mechanisms underlying the fetal adverse effects. We recently reported that combined MRI and PET technology allows the measurement of radioisotope distribution in maternal and fetal organs in pregnant Macaca radiata. Here, we evaluate the utility of PET to measure the uptake and distribution of (11)C-cocaine in the third-trimester fetus. Six pregnant M. radiata weighing 3.8-9.0 kg were anesthetized and MR images were acquired on a 4-T MRI instrument. In all 6 animals, dynamic PET scans were subsequently acquired using 148-259 MBq of (11)C-cocaine. Time-activity curves for both maternal and fetal organs were obtained simultaneously with the pregnant animal positioned transverse in the PET scanner. Distribution volume ratios for maternal a...

Annals of the New York Academy of Sciences, 1989

Clinical medicine. Reproductive health, 2008

Over the recent years there has been a gradual rise in the use of pharmaceuticals during pregnancy. Knowledge on placental drug transfer and metabolism has increased during the past decades as well. Investigation of the transplacental transfer of any therapeutically useful drug is essential to the understanding of its metabolic processes and is a prerequisite for its use during pregnancy. The purpose of this review is to give insight on the various techniques that have been developed to evaluate transplacental transfer of drugs and xenobiotics.

Journal of Nuclear Medicine, 2009

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. Methods: 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 5 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. Results: 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% 6 88% (P , 0.05) and 122% 6 75% (P , 0.05), respectively. Changes in other measured tissues were not statistically significant. Conclusion: 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.

Journal of Nuclear Medicine, 2013

ACS Chemical Neuroscience, 2016

While selective-serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed in the treatment of depression, their use during pregnancy leads to fetal drug exposures. According to recent reports, such exposures could affect fetal development and long-term offspring health. A central question is how pregnancy-induced physical and physiological changes in mothers, fetuses, and the placenta influence fetal SSRI exposures during gestation. In this study, we examined the effects of gestational stage on the maternal pharmacokinetics and fetal disposition of the SSRI (±)-citalopram (CIT) in a mouse model. We determined the maternal and fetal CIT serum concentration−time profiles following acute maternal administration on gestational days (GD)14 and GD18, as well as the fetal brain drug disposition. The results show that pregnancy affects the pharmacokinetics of CIT and that maternal drug clearance increases as gestation progresses. The data further show that CIT and its primary metabolite desmethylcitalopram (DCIT) readily cross the placenta into the fetal compartment, and fetal exposure to CIT exceeds that of the mother during gestation 2 h after maternal administration. Enzymatic activity assays revealed that fetal drug metabolic capacity develops in late gestation, resulting in elevated circulating and brain concentrations of DCIT at embryonic day (E)18. Fetal exposure to the SSRI CIT in murine pregnancy is therefore influenced by both maternal gestational stage and embryonic development, suggesting potential time-dependent effects on fetal brain development.

Journal of Pharmacokinetics and Pharmacodynamics, 2020

Drugs can have harmful effects on the embryo or fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of nonpregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Three examples were described to show how pregnancy PBPK can facilitate and guide dose assessment throughout gestation.

Journal of Nuclear Medicine, 2013

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. Methods: 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. Results: 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 (K 1 ) approximated tissue blood flow (Q); that is, extraction ratio (K 1 /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 [IC 50 ], 5.67 6 1.07 mM, vs. BPB IC 50 , 7.63 6 3.16 mM). Conclusion: 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-gpbased 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.

Current Drug Metabolism, 2009

Significant changes in the physiological and biotransformation processes that govern pharmacokinetics occur during pregnancy. Consequently, the disposition of many medications is altered in gestation and the efficacy and toxicity of drugs used by pregnant women can be difficult to predict or can lead to serious side effects. Gastrointestinal absorption and bioavailability of drugs vary due to changes in gastric secretion and small intestine motility. Various pregnancy-related hemodynamic changes such as an increase in cardiac output, blood volume, the volume of distribution (Vd), renal perfusion and glomerular filtration may affect drug disposition and elimination, and can cause increase or decrease in the terminal elimination half-life of drugs. Changes in maternal drug biotransformation activity also contribute to alterations in pharmacokinetics of drugs taken in pregnancy. Therefore, pregnant women may require different dosing regimens or their adjustment than both men and non-pregnant women. In addition, the prenatal pharmacotherapy is unique due to the presence of feto-placental unit. Considerations regarding transplacental pharmacokinetics and safety for the developing fetus are thus essential aspects of medication in pregnancy.

Journal of Radioanalytical and Nuclear Chemistry, 2006

Exposure to several environmental chemicals in utero is associated with subtle deleterious effects in cognitive, motor and behavioral functions. In order to assess in utero exposure to possible neurotoxins, fetal brain uptake of an exogenous compound given to a pregnant rhesus macaque was investigated using PET/CT imaging. CT clearly delineated the fetus which allowed the time course of the PET tracer in the fetal brain and other organs to be monitored. This study demonstrates the feasibility of quantifying the absolute fetal uptake of chemicals given systemically to the mother.