ABSTRACT
Choline is a new PET tracer, which uptake may occur via a choline-speciï¬c transporter protein and be accelerated during the proliferation of tumor cells. We report a 61-year-old woman with a metastatic pancreatic tumor from renal cell carcinoma, measuring 35×40 mm. PET scans demonstrated accumulation of 11C-choline in the metastatic pancreatic tumor, but no accumulation of 18F-FDG. Choline PET/CT may play a useful and complementary imaging modality, especially when FDG-PET/CT does not show expected findings or when the evaluation of tumor viability is needed, in patients with renal cell carcinoma.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Choline/chemistry , Fluorodeoxyglucose F18/analysis , Kidney Neoplasms/drug therapy , Positron Emission Tomography Computed Tomography/methods , Carcinoma, Renal Cell/complications , Female , Humans , Kidney Neoplasms/complications , Middle AgedABSTRACT
MKC-963, (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine, a potent inhibitor of platelet aggregation, was synthesized and used in clinical trials in the 1990s. In the process of clinical study, it was found that urinary excretion ratios for 6beta-hydroxycortisol and free cortisol increased significantly in parallel with decreases in the plasma concentrations of MKC-963 after repeated oral administration of the compound to healthy volunteers. These findings suggested that MKC-963 caused autoinduction (defined as the ability of a drug to induce enzymes that enhance its own metabolism, resulting in dispositional tolerance) in humans, and clinical studies using the compound were stopped. This experience prompted us to reevaluate the effects of this compound on CYP3A4 using primary human hepatocytes and cDNA-expressed human cytochrome P450 (P450) enzymes to determine whether the autoinduction of MKC-963 metabolism in humans could have been predicted if these in vitro systems had been used for the evaluation of MKC-963 in the preclinical study. The results of in vitro study showed that MKC-963 increased CYP3A4 mRNA expression level and activity of testosterone 6beta-hydroxylation to extents similar to those observed with rifampicin in primary human hepatocytes. In addition, approximately 90% of the MKC-963 metabolism in human liver microsomes was estimated to be attributable to CYP3A4. These in vitro findings are in good agreement with the results of clinical study, suggesting that studies using human hepatocytes and cDNA-expressed human P450s are useful for assessing the autoinductive nature of compounds under development before starting clinical studies.
Subject(s)
Cytochrome P-450 Enzyme System/biosynthesis , Drug Evaluation, Preclinical/methods , Hepatocytes/drug effects , Phthalazines/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Administration, Oral , Adult , Aged , Cells, Cultured , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/genetics , Enzyme Induction , Female , Hepatocytes/metabolism , Humans , Hydrocortisone/analogs & derivatives , Hydrocortisone/urine , Hydroxytestosterones/metabolism , Male , Phthalazines/administration & dosage , Phthalazines/pharmacokinetics , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacokinetics , RNA, Messenger/metabolism , Recombinant Proteins/metabolism , Treatment FailureABSTRACT
To obtain PET imaging of glucose metabolism in the brains of conscious rats, a method of rat head fixation was developed. PET measurement with microPET was performed for 60 min after 18F-FDG injection. Significant enhancement of glucose utilization in the right striatum was observed with infusion of Rp-adenosine-3,5-cyclic phosphorothioate triethylamine (Rp-cAMPS). FDG uptake increments were also seen in the ipsilateral frontal cortex and thalamus. As initial FDG uptake in the brain was not significantly altered by Rp-cAMPS, increased glucose metabolism might be due to an increase in the phosphorylation rate by hexokinase rather than the delivery process from plasma to the brain. In contrast to awake rats, the effect of Rp-cAMPS was abolished by anesthesia using chloral hydrate, indicating that neuronal activity has an important role in short term regulation of hexokinase activity through the cAMP/PKA system in the brain. These results strongly demonstrated the value of measuring glucose utilization in the brains of conscious rats.
Subject(s)
Brain Mapping/methods , Brain/diagnostic imaging , Cyclic AMP/analogs & derivatives , Fluorodeoxyglucose F18/metabolism , Positron-Emission Tomography/methods , Protein Kinase Inhibitors/pharmacology , Thionucleotides/pharmacology , Anesthetics/pharmacology , Animals , Blood Glucose/metabolism , Brain/drug effects , Brain/metabolism , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Cyclic AMP/pharmacology , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Functional Laterality/physiology , Male , Metabolic Clearance Rate , Models, Animal , Radiopharmaceuticals/pharmacology , Rats , Rats, Wistar , Thalamus/drug effects , Thalamus/metabolism , Wakefulness/drug effects , Wakefulness/physiologyABSTRACT
Dihydropyridin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide inhibition assay. Compounds 1, 4, 5 and 7-11 exhibited potent activity in the inducible nitric oxide (iNOS) inhibition assay. Of these 5, 6, 9 and 10 showed 5- to 11-fold increases in isoform selectivity. Compounds 1, 5, 9 and 10 showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 5 also showed good bioavailability (BA) when given orally.
Subject(s)
Dihydropyridines/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Nitric Oxide Synthase/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Dihydropyridines/chemical synthesis , Dihydropyridines/pharmacology , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imines/chemical synthesis , Imines/pharmacokinetics , Imines/pharmacology , Lipopolysaccharides/administration & dosage , Maximum Tolerated Dose , Mice , Nitric Oxide/blood , Nitric Oxide Synthase Type II , Structure-Activity RelationshipABSTRACT
In this study, we performed a screening of the specificities of rat cytochrome P450 (CYP) isoforms for metabolic reactions known as the specific probes of human CYP isoforms, using 13 rat CYP isoforms expressed in baculovirus-infected insect cells or B-lymphoblastoid cells. Among the metabolic reactions studied, diclofenac 4-hydroxylation (DFH), dextromethorphan O-demethylation (DMOD) and midazolam 4-hydroxylation were specifically catalyzed by CYP2C6, CYP2D2 and CYP3A1/3A2, respectively. These results suggest that diclofenac 4-hydroxylation, dextromethorphan O-demethylation and midazolam 4-hydroxylation are useful as catalytic markers of CYP2C6, CYP2D2 and CYP3A1/3A2, respectively. On the other hand, phenacetin O-deethylation and 7-ethoxyresorufin O-deethylation were catalyzed both by CYP1A2 and by CYP2C6. Benzyloxyresorufin O-dealkylation and pentoxyresorufin O-dealkylation were also catalyzed by CYP1A2 in addition to CYP2B1. Bufuralol 1'-hydroxylation was extensively catalyzed by CYP2D2 but also by CYP2C6 and CYP2C11. p-Nitrophenol 2-hydroxylation and chlorzoxazone 6-hydroxylation were extensively catalyzed by CYP2E1 but also by CYP1A2 and CYP3A1. Therefore, it is necessary to conduct further study to clarify whether these activities in rat liver microsomes are useful as probes of rat CYP isoforms. In contrast, coumarin 7-hydroxylation and S- and R-mephenytoin 4'-hydroxylation did not show selectivity toward any isoforms of rat CYP studied. Therefore, activities of coumarin 7-hydroxylation and S- and R-mephenytoin 4'-hydroxylation are not able to be used as catalytic probes of CYP isoforms in rat liver microsomes. These results may provide useful information regarding catalytic probes of rat CYPs for studies using rat liver microsomal samples.