ABSTRACT
We aimed to determine a detailed regional ventricular distribution pattern of the novel cardiac nerve PET radiotracer 18F-LMI1195 in healthy rabbits. Ex-vivo high resolution autoradiographic imaging was conducted to identify accurate ventricular distribution of 18F-LMI1195. In healthy rabbits, 18F-LMI1195 was administered followed by the reference perfusion marker 201Tl for a dual-radiotracer analysis. After 20 min of 18F-LMI1195 distribution time, the rabbits were euthanized, the hearts were extracted, frozen, and cut into 20-µm short axis slices. Subsequently, the short axis sections were exposed to a phosphor imaging plate to determine 18F-LMI1195 distribution (exposure for 3 h). After complete 18F decay, sections were re-exposed to determine 201Tl distribution (exposure for 7 days). For quantitative analysis, segmental regions of Interest (ROIs) were divided into four left ventricular (LV) and a right ventricular (RV) segment on mid-ventricular short axis sections. Subendocardial, mid-portion, and subepicardial ROIs were placed on the LV lateral wall. 18F-LMI1195 distribution was almost homogeneous throughout the LV wall without any significant differences in all four LV ROIs (anterior, posterior, septal and lateral wall, 99 ± 2, 94 ± 5, 94 ± 4 and 97 ± 3%LV, respectively, n.s.). Subepicardial 201Tl uptake was significantly lower compared to the subendocardial portion (subendocardial, mid-portion, and subepicardial activity: 90 ± 3, 96 ± 2 and *80 ± 5%LV, respectively, *p < 0.01 vs. mid-portion). This was in contradistinction to the transmural wall profile of 18F-LMI1195 (90 ± 4, 96 ± 5 and 84 ± 4%LV, n.s.). A slight but significant discrepant transmural radiotracer distribution pattern of 201Tl in comparison to 18F-LMI1195 may be a reflection of physiological sympathetic innervation and perfusion in rabbit hearts.
Subject(s)
Fluorine Radioisotopes/pharmacokinetics , Fluorobenzenes/pharmacokinetics , Guanidines/pharmacokinetics , Heart Ventricles/chemistry , Myocardium/metabolism , Animals , Autoradiography/methods , Heart Ventricles/metabolism , Male , Rabbits , Radiopharmaceuticals/pharmacokinetics , Sympathetic Nervous System/physiologySubject(s)
Cardiomyopathies/diagnostic imaging , Ephedrine/analogs & derivatives , Fluorobenzenes/pharmacokinetics , Guanidines/pharmacokinetics , Myocardial Ischemia/diagnostic imaging , Positron Emission Tomography Computed Tomography , Sympathetic Nervous System/diagnostic imaging , Aged , Ephedrine/pharmacokinetics , Humans , Male , Risk , ST Elevation Myocardial Infarction/diagnostic imagingABSTRACT
PURPOSE: 4-[18F]Fluorobenzylguanidine ([18F]PFBG) is a positron emission tomography (PET) probe for non-invasive targeting of the norepinephrine transporter. The aim of this study was to assess uptake and distribution characteristics of this PET probe. PROCEDURES: Three cynomolgus monkeys were injected with 269 ± 51 MBq (7.3 ± 1.4 mCi) of [18F]PFBG and 21 whole body PET scans were acquired over 165 min. s around organs to generate time-activity curves. The absorbed doses to individual organs and the effective dose to the whole body were estimated. RESULTS: Favorable distribution of [18F]PFBG was noted with a fast wash-in and wash-out of radioactivity from several tissues. [18F]PFBG rapidly distributed in the heart, liver, kidneys, and adrenal glands. The uptake presented as %ID in the brain, lung, and spleen was 1.06 ± 0.45, 6.28 ± 0.33, and 1.39 ± 0.35 at 1 min and decreased to 0.29 ± 0.02, 1.78 ± 0.31, and 0.66 ± 0.22 by 112 min. In general, a two- to fourfold reduction was noted from peak radioactivity levels. Rapid uptake and significant retention of radioactivity was noted in the heart and the septal wall was distinctly visible by 20 min. Fast wash-in and washout kinetics for [18F]PFBG resulted in shorter residence times. The residence time for the liver, lungs, kidneys, and spleen were 28.01 ± 7.73 min, 2.97 ± 0.56 min, 6.04 ± 3.41 min, and 1.09 ± 0.33 min, respectively. The mean effective dose for the 70-kg male was 0.04 ± 0.00 mSv/MBq. The organs receiving the highest radiation dose in the 70-kg male model were the testes (0.11 ± 0.02 mGy/MBq), adrenals (0.08 ± 0.01 mGy/MBq), and urinary bladder wall (0.08 ± 0.01 mGy/MBq). CONCLUSIONS: [18F]PFBG shows a favorable biodistribution pattern. Rapid and persistent uptake was noted in innervated organs. Renal clearance was the major path for elimination of [18F]PFBG. The estimated radiation burden from [18F]PFBG was significantly lower than that from [124I]MIBG.
Subject(s)
Fluorobenzenes/chemistry , Guanidines/chemistry , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Positron-Emission Tomography , Radiometry , Whole Body Imaging , Animals , Fluorobenzenes/pharmacokinetics , Guanidines/pharmacokinetics , Macaca fascicularis , Male , Radioactivity , Time Factors , Tissue DistributionABSTRACT
BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.
Subject(s)
Benzamides/administration & dosage , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Emulsions/chemistry , Excipients/chemistry , Fluorobenzenes/administration & dosage , Lipids/chemistry , Administration, Oral , Animals , Benzamides/adverse effects , Benzamides/pharmacokinetics , Biological Availability , Dogs , Drug Compounding , Drug Stability , Fluorobenzenes/adverse effects , Fluorobenzenes/pharmacokinetics , Macaca fascicularis , Male , Mice, Inbred BALB C , Olive Oil/chemistry , Solubility , Triglycerides/chemistry , Water/chemistryABSTRACT
1. 14 C-Labelled E/Z isomers of a synthetic pyrethroid metofluthrin ((E/Z)-(1 R,3 R)-2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate, abbreviated as RTE/RTZ, respectively) were used for rat metabolism studies. 14 C-RTE or RTZ labelled at the carbonyl-carbon [acid-14C] or the methoxymethylbenzyl-α-carbon [alcohol-14 C] was administered orally to rats at 1 and 20 mg/kg. 2. Dosed compounds were mostly absorbed, metabolised, and rapidly excreted. Dose-related increase in blood AUC suggested no saturation of absorption at the high dose. Blood 14 C was maximal at 3-8 h and decreased with a half-life of 52-163 h. Radioactivity in tissues, blood and plasma decreased basically at the same rate and the sum fell below 0.2% of the dose at 168 h. 3. Although the major metabolic pathways of the isomers, that is, ester cleavage, O-demethylation and ω-oxidation, were similar, there was a notable difference. The RTZ double bond commonly undergoes epoxidation while RTE double bond mainly undergoes glutathione conjugation, which causes faster elimination from plasma and greater excretion into faeces on RTE. Faster urinary excretion and elimination from blood were observed for the alcohol moiety than the acid moiety. 4. In conclusion, this study described the overall metabolic profiles of metofluthrin and identified the differences in metabolic breakdown between the isomers. No marked sex-/dose-related differences were observed.
Subject(s)
Cyclopropanes/pharmacokinetics , Fluorobenzenes/pharmacokinetics , Insecticides/pharmacokinetics , Animals , Bile/chemistry , Bile/drug effects , Carbon Radioisotopes/analysis , Cyclopropanes/chemistry , Cyclopropanes/metabolism , Feces/chemistry , Female , Fluorobenzenes/chemistry , Fluorobenzenes/metabolism , Insecticides/chemistry , Insecticides/metabolism , Isomerism , Male , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain.
Subject(s)
Benzylamines/pharmacokinetics , Brain/drug effects , Brain/diagnostic imaging , Fenfluramine/pharmacology , Phenethylamines/pharmacokinetics , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin Agents/pharmacology , Adamantane/analogs & derivatives , Adamantane/pharmacokinetics , Aminoquinolines/pharmacokinetics , Animals , Brain Mapping , Dose-Response Relationship, Drug , Female , Fenfluramine/blood , Fluorobenzenes/pharmacokinetics , Macaca mulatta , Magnetic Resonance Imaging , Piperidines/pharmacokinetics , Positron-Emission Tomography , Protein Binding/drug effects , Purinergic P2X Receptor Antagonists/pharmacokineticsSubject(s)
Humans , Male , Female , Aged , Aged, 80 and over , Clarithromycin/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Pyrimidines/metabolism , Pyrimidines/therapeutic use , Pyrimidines/pharmacokinetics , Rhabdomyolysis/chemically induced , Sulfonamides/metabolism , Sulfonamides/therapeutic use , Sulfonamides/pharmacokinetics , Fatty Acids, Monounsaturated/metabolism , Fatty Acids, Monounsaturated/therapeutic use , Fatty Acids, Monounsaturated/pharmacokinetics , Pravastatin/metabolism , Pravastatin/therapeutic use , Pravastatin/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Organic Anion Transporters , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Liver-Specific Organic Anion Transporter 1 , Drug Interactions , Acute Kidney Injury/chemically induced , Rosuvastatin Calcium , Fluorobenzenes/metabolism , Fluorobenzenes/therapeutic use , Fluorobenzenes/pharmacokinetics , Solute Carrier Organic Anion Transporter Family Member 1B3 , Fluvastatin , Hyperkalemia/chemically induced , Indoles/metabolism , Indoles/therapeutic use , Indoles/pharmacokineticsABSTRACT
When [benzyl-α-(14)C]-labeled (Z)-(1R,3R)-profluthrin (2,3,5,6-tetrafluoro-4-methylbenzyl (Z)-(1R,3R)-2,2-dimethyl-3-(prop-1-enyl) cyclopropanecarboxylate, a newly developed pyrethroid) was administered orally to rats at 1 mg/kg, around 70% was absorbed, metabolized, and mainly excreted into urine within 48 h. Radioactivity in plasma reached Cmax at 6-8 h, and decreased (half-life; 37-52 h). A similar tendency was observed also in tissues. Absorption rate was slightly lower at high dose, while kinetics and distribution did not change. Eight metabolites were detected in urine and one in feces. Most of the (14)C in feces was unabsorbed (Z)-(1R,3R)-profluthrin. The main metabolic reactions were ester cleavage, hydroxylation of the methyl group on the C4-position of the benzene ring, and its glucuronidation or oxidation to carboxylic acid. Oxidation of the geminal dimethyl on the cyclopropane-C2 to carboxylic acid, oxidation followed by hydration of the propenyl double bond, and ω-oxidation to carboxylic acid and mercapturic acid conjugation of the benzyl alcohol were observed as minor reactions.
Subject(s)
Fluorobenzenes/pharmacokinetics , Insecticides/pharmacokinetics , Pyrethrins/pharmacokinetics , Animals , Female , Fluorobenzenes/administration & dosage , Fluorobenzenes/urine , Insecticides/administration & dosage , Insecticides/urine , Male , Pyrethrins/administration & dosage , Pyrethrins/urine , Rats , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
The article gives a definition of highly variable drugs, describes currently existing regulatory guidance and approaches to the study of bioequivalence of highly variable drugs, and formulates recommendations on the design and evaluation of the results of studies of such drugs. These aspects are considered by the example of calculations based on actual data from the registration dossiers materials for rosuvastatin.
Subject(s)
Clinical Trials as Topic , Fluorobenzenes/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Models, Biological , Pyrimidines/pharmacokinetics , Sulfonamides/pharmacokinetics , Humans , Rosuvastatin CalciumABSTRACT
UNLABELLED: (18)F-N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine ((18)F-LMI1195) is a new PET tracer designed for noninvasive assessment of sympathetic innervation of the heart. The (18)F label facilitates the imaging advantages of PET over SPECT technology while allowing centralized manufacturing. Highly specific neural uptake of (18)F-LMI1195 has previously been established, but the retention kinetics are not yet fully understood. METHODS: Healthy New Zealand White rabbits were studied with (18)F-LMI1195 using a small-animal PET system. Dynamic 40-min chest scans were started just before intravenous bolus injection of (18)F-LMI1195. Imaging was performed under norepinephrine transport inhibition with desipramine pretreatment, a 1.5 mg/kg desipramine chase administered 10 min after tracer injection, and saline treatment of controls. As a reference, cardiac uptake of (11)C-hydroxyephedrine and (123)I-metaiodobenzylguanidine ((123)I-MIBG) was examined by PET and planar scintigraphy, respectively. RESULTS: Cardiac uptake of all 3 tracers was inhibited by pretreatment with desipramine. Stable cardiac tracer retention was delineated by dynamic PET in control rabbits for (11)C-hydroxyephedrine (washout rate, 0.42% ± 0.57%/min) and (18)F-LMI1195 (washout rate, 0.058% ± 0.28%/min). A desipramine chase increased (11)C-hydroxyephedrine washout from the heart (2.43% ± 0.15%/min, P < 0.001), whereas (18)F-LMI1195 washout was not influenced (0.059% ± 0.11%/min, not statistically significant). Additionally, a desipramine chase did not change the cardiac (123)I-MIBG uptake (delayed heart-to-mediastinum ratio, 1.99 ± 0.12 (desipramine chase) vs. 2.05 ± 0.16 (controls), not statistically significant). CONCLUSION: In vivo norepinephrine transporter (NET) blockade with desipramine confirmed specific neural uptake of (18)F-LMI1195, (11)C-hydroxyephedrine, and (123)I-MIBG in rabbit hearts. (11)C-hydroxyephedrine cardiac retention was sensitive to a NET inhibitor chase, indicating a cycle of continuous NET uptake and release at the nerve terminals. In contrast, (18)F-LMI1195 and (123)I-MIBG demonstrated stable storage at the nerve terminal with resistance to a NET inhibitor chase, mimicking physiologic norepinephrine turnover.
Subject(s)
3-Iodobenzylguanidine/pharmacokinetics , Autonomic Nervous System Diseases/metabolism , Ephedrine/analogs & derivatives , Fluorine Radioisotopes/pharmacokinetics , Fluorobenzenes/pharmacokinetics , Guanidines/pharmacokinetics , Positron-Emission Tomography/methods , Animals , Autonomic Nervous System Diseases/diagnostic imaging , Ephedrine/pharmacokinetics , Fluorine Radioisotopes/chemistry , Isotope Labeling/methods , Kinetics , Metabolic Clearance Rate , Organ Specificity , Rabbits , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Tissue DistributionABSTRACT
Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor used to lower blood low-density lipoprotein cholesterol, is a substrate of the membrane ABCG2 exporter. ABCG2 variants have been shown to alter rosuvastatin disposition. The objective of this study is to determine the impact of ABCG2 34/421 compound haplotypes on rosuvastatin pharmacokinetics in healthy Chinese volunteer subjects. Eight hundred healthy Chinese males were genotyped by polymerase chain reaction-pyrosequencing for ABCG2 34G>A, ABCG2 421C>A, SLCO1B1 521T>C, and CYP2C9*3 variants. Sixty-two male subjects with wild-type SLCO1B1 c.521TT and CYP2C9*3 were recruited for this pharmacokinetic study of rosuvastatin. A single oral dose of 10 mg rosuvastatin was administrated to each subject, and blood samples were collected before and at various time points after drug administration. Plasma concentration of rosuvastatin was determined by high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was carried out using the WinNonlin program. In Chinese males, high allele frequency of ABCG2 c.34G>A (0.275) and c.421C>A (0.282) was observed, resulting in a considerable portion (23.3%) of subjects being ABCG2 34/421 compound heterozygotes. Compared with subjects with ABCG2 wild-type (c.34GG/421CC), plasma rosuvastatin Cmax and area under the curve, AUC0-∞, were significantly higher, while the apparent oral clearance, CL/F, was significantly lower in subjects with c.34AA, c.421AA, and c.34GA/421CA genotypes. Both t1/2 and Tmax were similar among subjects with different genotypes. A high frequency of ABCG2 c.34G>A and c.421C>A variants was present in Chinese males, and the disposition of rosuvastatin was significantly affected by both variants. These data suggest that it is advisable to genotype these variants when prescribing rosuvastatin to Chinese subjects, leading to a precise dose for each individual.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Asian People/genetics , Fluorobenzenes/pharmacokinetics , Genetic Variation/genetics , Neoplasm Proteins/genetics , Pyrimidines/pharmacokinetics , Sulfonamides/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Adolescent , Adult , Cytochrome P-450 CYP2C9/genetics , Gene Frequency/drug effects , Gene Frequency/genetics , Genetic Variation/drug effects , Genotype , Heterozygote , Homozygote , Humans , Liver-Specific Organic Anion Transporter 1 , Male , Organic Anion Transporters/genetics , Rosuvastatin Calcium , Young AdultABSTRACT
The Dutch campaign 'Verstandig kiezen', based on the American programme 'Choosing wisely', aims to improve quality in healthcare, with attention to cost control. The 'Choosing wisely'-based programme can be applied in the choice of a statin. Atorvastatin and rosuvastatin are regarded as equal choices in various guidelines regarding cardiovascular risk management. Generic atorvastatin is available, and is approximately 25 times cheaper than rosuvastatin in almost equipotent doses. Rosuvastatin provides a greater LDL reduction than atorvastatin. Patient LDL targets can usually be achieved with atorvastatin, and rosuvastatin is not needed. At group level, there are no relevant differences in adverse-events profile between both statins. Atorvastatin and rosuvastatin do have different pharmacokinetic interactions. When changing medication, good provision of information is a prerequisite for patient satisfaction and compliance. We advise use of atorvastatin instead of rosuvastatin as drug of choice when the LDL target is not reached using simvastatin. However, under specific conditions, rosuvastatin should be the treatment of choice. Efficacy and adverse effects should then be evaluated at individual patient level.
Subject(s)
Cardiovascular Diseases/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Quality of Health Care , Atorvastatin , Fluorobenzenes/economics , Fluorobenzenes/pharmacokinetics , Fluorobenzenes/therapeutic use , Health Care Costs , Heptanoic Acids/economics , Heptanoic Acids/pharmacokinetics , Heptanoic Acids/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/economics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Pyrimidines/economics , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Pyrroles/economics , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Risk Factors , Rosuvastatin Calcium , Simvastatin/economics , Simvastatin/pharmacokinetics , Simvastatin/therapeutic use , Sulfonamides/economics , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
Atherosclerotic diseases are common in pet psittacine birds, in particular Amazon parrots. While hypercholesterolemia and dyslipidemia have not definitely been associated with increased susceptibility to atherosclerosis in parrots, these are important and well-known risk factors in humans. Therefore statin drugs such as rosuvastatin constitute the mainstay of human treatment of dyslipidemia and the prevention of atherosclerosis. No pharmacologic studies have been performed in psittacine birds despite the high prevalence of atherosclerosis in captivity. Thirteen Hispaniolan Amazon parrots were used to test a single oral dose of 10 mg/kg of rosuvastatin with blood sampling performed according to a balanced incomplete block design over 36 hours. Because low plasma concentrations were produced in the first study, a subsequent pilot study using a dose of 25 mg/kg in 2 Amazon parrots was performed. Most plasma samples for the 10 mg/kg dose and all samples for the 25 mg/kg dose had rosuvastatin concentration below the limits of quantitation. For the 10 mg/kg study, the median peak plasma concentration and time to peak plasma concentration were 0.032 µg/mL and 2 hours, respectively. Our results indicate that rosuvastatin does not appear suitable in Amazon parrots as compounded and used at the dose in this study. Pharmacodynamic studies investigating lipid-lowering effects of statins rather than pharmacokinetic studies may be more practical and cost effective in future studies to screen for a statin with more ideal properties for potential use in psittacine dyslipidemia and atherosclerotic diseases.
Subject(s)
Amazona/blood , Fluorobenzenes/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Pyrimidines/pharmacokinetics , Sulfonamides/pharmacokinetics , Administration, Oral , Animals , Fluorobenzenes/administration & dosage , Fluorobenzenes/blood , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Pyrimidines/administration & dosage , Pyrimidines/blood , Rosuvastatin Calcium , Sulfonamides/administration & dosage , Sulfonamides/bloodABSTRACT
Organic anion transporting polypeptides (OATPs) mediate hepatic drug uptake and serve as the loci of drug-drug interactions (DDIs). Consequently, there is a major need to develop animal models and refine in vitro-in vivo extrapolations. Therefore, the in vivo disposition of a model OATP substrate, [(3)H]rosuvastatin (RSV), was studied in the cynomolgus monkey and reported for the first time. After monkeys had received a 3-mg/kg oral dose, mass balance was achieved after bile duct cannulation (mean total recovery of radioactivity of 103.6%). Forty-two percent of the RSV dose was recovered in urine and bile, and the elimination pathways were similar to those reported for human subjects; 61.7%, 39.0%, and 2.9% of the dose was recovered in the feces, bile, and urine, respectively. The high levels of unchanged RSV recovered in urine and bile (26% of the dose) and the relatively low levels of metabolites observed indicated that RSV was eliminated largely by excretion. Also, for the first time, the in vitro inhibitory potential of cyclosporin A (CsA) toward cynomolgus monkey OATPs and sodium-taurocholate cotransporting polypeptide was studied in vitro (primary hepatocytes and transporter-transfected cells). It is concluded that one can study the CsA-RSV DDI in the cynomolgus monkey. For example, the in vitro IC50 values were within 2-fold (monkey versus human), and the increase (versus vehicle control) in the RSV AUC0-inf (6.3-fold) and Cmax (10.2-fold) with CsA (100 mg/kg) was similar to that reported for humans. The results further support the use of the cynomolgus monkey as a model to assess interactions involving OATP inhibition.
Subject(s)
Fluorobenzenes/metabolism , Molecular Probes/metabolism , Organic Anion Transporters/metabolism , Pyrimidines/metabolism , Sulfonamides/metabolism , Animals , Bile/metabolism , Biological Transport/drug effects , Cyclosporine/pharmacology , Feces/chemistry , Fluorobenzenes/pharmacokinetics , Fluorobenzenes/urine , HEK293 Cells , Humans , Isotope Labeling , Macaca fascicularis , Male , Molecular Probes/pharmacokinetics , Molecular Probes/urine , Organic Anion Transporters, Sodium-Dependent/metabolism , Pyrimidines/pharmacokinetics , Pyrimidines/urine , Rosuvastatin Calcium , Species Specificity , Sulfonamides/pharmacokinetics , Sulfonamides/urine , Symporters/metabolismABSTRACT
OBJECTIVE: An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. METHODS: The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. RESULTS: Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 µM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17ß glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 µM, 3.34 ± 0.64 µM, and 0.973 ± 0.11 µM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. CONCLUSION: These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.
Subject(s)
Acetates/pharmacokinetics , Aminopyridines/pharmacokinetics , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Fluorobenzenes/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Membrane Transport Proteins/drug effects , Pyrimidines/pharmacokinetics , Sulfonamides/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/metabolism , Acetates/administration & dosage , Acetates/blood , Adult , Aminopyridines/administration & dosage , Aminopyridines/blood , Area Under Curve , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Interactions , Female , Fluorobenzenes/administration & dosage , Fluorobenzenes/blood , Healthy Volunteers , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Liver-Specific Organic Anion Transporter 1 , Male , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Metabolic Clearance Rate , Middle Aged , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Organic Anion Transporters/antagonists & inhibitors , Organic Anion Transporters/metabolism , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Organic Anion Transporters, Sodium-Independent/metabolism , Pyrimidines/administration & dosage , Pyrimidines/blood , Risk Assessment , Rosuvastatin Calcium , Solute Carrier Organic Anion Transporter Family Member 1B3 , Sulfonamides/administration & dosage , Sulfonamides/blood , Transfection , Young AdultSubject(s)
Fluorobenzenes/pharmacokinetics , Guanidines/pharmacokinetics , Heart/diagnostic imaging , Heart/innervation , Myocardium/metabolism , Radiopharmaceuticals/pharmacokinetics , Sympathetic Nervous System/diagnostic imaging , Sympathetic Nervous System/metabolism , Adrenergic Uptake Inhibitors/pharmacology , Animals , Electric Stimulation , Fluorobenzenes/administration & dosage , Guanidines/administration & dosage , Isolated Heart Preparation , Norepinephrine/metabolism , Rabbits , Radionuclide Imaging , Radiopharmaceuticals/administration & dosage , Sympathetic Nervous System/drug effects , Tissue DistributionABSTRACT
Individual differences in coping style emerge as a function of underlying variability in the activation of a mesocorticolimbic brain circuitry. Particularly serotonin seems to play an important role. For this reason, we assessed serotonin-2A receptor (5-HT2A R) binding in the brain of rats with different coping styles. We compared proactive and reactive males of two rat strains, Wild-type Groningen (WTG) and Roman high- and low avoidance (RHA, RLA). 5-HT2A R binding in (pre)frontal cortex (FC) and hippocampus was investigated using a radiolabeled antagonist ([(3) H]MDL-100907) and agonist ([(3) H]Cimbi-36) in binding assays. No differences in 5-HT2A R binding were observed in male animals with different coping styles. [(3) H]MDL-100907 displayed a higher specific-to-nonspecific binding ratio than [(3) H]Cimbi-36. Our findings suggest that in these particular rat strains, 5-HT2A R binding is not an important molecular marker for coping style. Because neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5-HT2A R is co-varying with levels of aggression or active avoidance in WTG, RHA and RLA.
Subject(s)
Adaptation, Psychological/drug effects , Aggression/physiology , Brain/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Animals , Avoidance Learning/physiology , Benzylamines/pharmacokinetics , Brain/drug effects , Fluorobenzenes/pharmacokinetics , Male , Phenethylamines/pharmacokinetics , Piperidines/pharmacokinetics , Protein Binding/drug effects , Protein Binding/genetics , Rats , Rats, Inbred Strains , Serotonin/metabolism , Serotonin Antagonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacokinetics , Tritium/pharmacokineticsABSTRACT
CONTEXT: A fluorine-containing pyrethroid metofluthrin is widely used recently in mosquito repellents. OBJECTIVE: The urinary excretion kinetics of its metabolites was evaluated in rats to establish an optimal biomarker for monitoring metofluthrin exposure of the general population. METHODS AND RESULTS: After metofluthrin had been administered intraperitoneally to rats, the urinary excretion kinetics of the major metofluthrin metabolites was evaluated by moment analysis. The urinary excretion amounts of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol were estimated to be proportional to the absorption amounts over a wide exposure range. CONCLUSION: Urinary 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was considered to be an optimal biomarker for metofluthrin exposure.
Subject(s)
Benzyl Alcohols/urine , Cyclopropanes/pharmacokinetics , Fluorobenzenes/pharmacokinetics , Fluorobenzenes/urine , Insect Repellents/pharmacokinetics , Animals , Biomarkers/urine , Male , Rats, Sprague-DawleyABSTRACT
BACKGROUND: The cytochrome P450 3A4 (CYP3A4) inhibitor clarithromycin may also inhibit liver-specific organic anion-transporting polypeptides (OATP1B1 and OATP1B3). We studied whether concurrent use of clarithromycin and a statin not metabolized by CYP3A4 was associated with an increased frequency of serious adverse events. METHODS: Using large health care databases, we studied a population-based cohort of older adults (mean age 74 years) who were taking a statin not metabolized by CYP3A4 (rosuvastatin [76% of prescriptions], pravastatin [21%] or fluvastatin [3%]) between 2002 and 2013 and were newly prescribed clarithromycin (n=51,523) or azithromycin (n=52,518), the latter an antibiotic that inhibits neither CYP3A4 nor OATP1B1 and OATP1B3. Outcomes were hospital admission with a diagnostic code for rhabdomyolysis, acute kidney injury or hyperkalemia, and all-cause mortality. All outcomes were assessed within 30 days after co-prescription. RESULTS: Compared with the control group, patients co-prescribed clarithromycin and a statin not metabolized by CYP3A4 were at increased risk of hospital admission with acute kidney injury (adjusted relative risk [RR] 1.65, 95% confidence interval [CI] 1.31 to 2.09), admission with hyperkalemia (adjusted RR 2.17, 95% CI 1.22 to 3.86) and all-cause mortality (adjusted RR 1.43, 95% CI 1.15 to 1.76). The adjusted RR for admission with rhabdomyolysis was 2.27 (95% CI 0.86 to 5.96). The absolute increase in risk for each outcome was small and likely below 1%, even after we considered the insensitivity of some hospital database codes. INTERPRETATION: Among older adults taking a statin not metabolized by CYP3A4, co-prescription of clarithromycin versus azithromycin was associated with a modest but statistically significant increase in the 30-day absolute risk of adverse outcomes.
Subject(s)
Clarithromycin/adverse effects , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Acute Kidney Injury/chemically induced , Aged , Aged, 80 and over , Drug Interactions , Fatty Acids, Monounsaturated/metabolism , Fatty Acids, Monounsaturated/pharmacokinetics , Fatty Acids, Monounsaturated/therapeutic use , Female , Fluorobenzenes/metabolism , Fluorobenzenes/pharmacokinetics , Fluorobenzenes/therapeutic use , Fluvastatin , Humans , Hyperkalemia/chemically induced , Indoles/metabolism , Indoles/pharmacokinetics , Indoles/therapeutic use , Liver-Specific Organic Anion Transporter 1 , Male , Organic Anion Transporters , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Pravastatin/metabolism , Pravastatin/pharmacokinetics , Pravastatin/therapeutic use , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Retrospective Studies , Rhabdomyolysis/chemically induced , Rosuvastatin Calcium , Solute Carrier Organic Anion Transporter Family Member 1B3 , Sulfonamides/metabolism , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
Stringent requirements are in place for the evaluation and registration of new compounds with biocidal or pesticidal activities. However, the registration requirements for established compounds from new suppliers or for established compounds produced by a different manufacturing process have been less clear and ambiguity exists as to how 'equivalence of health hazards' can unequivocally be demonstrated analytically and by toxicological assays. The case presented in this analysis focuses on the chiral pyrethroid transfluthrin (TFL) synthesized by esterification of an acid chloride and alcoholic moiety. According to any modifications of the process of synthesis and purification, new potentially highly toxic and yet chemically reactive impurities in low concentrations (<0.1%) may be formed. Amongst these, that with the structural alert 'organic acid anhydride' was given heightened concern as the most potent putative toxicologically significant impurity. The course taken in this analysis focused on the comparison of reference TFL with commercialized generic TFL from two alternative manufacturing sources in India and China. Despite their apparent high racemic purity, TFLs from generic sources were biologically less effective, genotoxic in the Ames' assay, demonstrated sensory lung irritation and lung/skin sensitization in specialized bioassays. While the off-patent reference TFL was unequivocally negative in all assays (anhydride content not detectable, LOQ <0.01%), positive results with high batch-to-batch variability were a frequent outcome in generic TFLs. Tier I analytical assays failed to detect this relevant impurity in the absence of impurity-specific optimized analytical procedures. This finding suggests that a well-balanced combined approach of analytical and toxicological assays provides the best means to assure that all critical impurities are identified and accounted for. Similarly, putative 'structural alert'-based toxicity tests proved to be more predictive than any indiscriminant battery of standard bioassays commonly applied to demonstrate equivalence, such as acute oral/dermal toxicity and/or eye/skin irritation assays.