RESUMO
A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.
Assuntos
Proteínas de Transporte/metabolismo , Citocromo P-450 CYP3A/metabolismo , Combinação de Medicamentos , Interações Medicamentosas , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Área Sob a Curva , Proteínas de Transporte/antagonistas & inibidores , Linhagem Celular , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/enzimologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Farmacocinética , Distribuição Tecidual , Adulto JovemRESUMO
OBJECTIVE: To examine if concomitant administration of furosemide, a loop diuretic, with the potassium- and magnesium-sparing diuretic triamterene would decrease loss of potassium and magnesium while improving diuresis. METHODS: In this open-label, three-way crossover study, healthy subjects were randomized to receive treatment with 40 mg furosemide, with 150 mg triamterene, or treatment with 40 mg furosemide and 150 mg triamterene. Urine samples were collected 24 hours before dosing and between 0 - 1, 1 - 2, 2 - 3, 3 - 4, 4 - 6, 6 - 8, 8 - 12, and 12 - 24 hours post-dosing. Sodium and potassium levels were measured by an ion-selective electrode method. Magnesium was measured colorimetrically using a xylidyl blue reaction. RESULTS: Co-administration of furosemide with triamterene resulted in enhanced diuresis, particularly in the first 0 - 12 hours post-dose, compared with either furosemide or triamterene alone. Compared to individual treatments, combination therapy significantly increased urinary sodium excretion (p = 0.0001) while significantly decreasing urinary potassium excretion (p = 0.0001); importantly, the magnesium-sparing characteristic of triamterene was retained with furosemide co-administration. CONCLUSION: Triamterene, when used in combination with the loop diuretic, furosemide, preserves intracellular potassium and magnesium while enhancing the natriuretic effect of furosemide.
Assuntos
Diurese/efeitos dos fármacos , Diuréticos/farmacologia , Furosemida/farmacologia , Triantereno/farmacologia , Adolescente , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Magnésio/urina , Masculino , Potássio/urina , Sódio/urinaRESUMO
UNLABELLED: 123I-Labeled iodoazomycin arabinoside (IAZA) is a marker of hypoxia in vivo. It has been used clinically to image hypoxic tissue in solid tumors, peripheral vascular disease of diabetic origin, blunt brain trauma, and rheumatoid joints and in an animal model of cerebrovascular disease. The radiation dose biodistribution for 123I-IAZA was studied to assess and characterize its suitability as a clinical radiopharmaceutical. METHODS: Six healthy volunteers each received a nominal 185-MBq (5 mCi) dose of 123I-IAZA administered as a slow (1-3 min) intravenous injection in the arm. Anterior and posterior whole-body planar images were acquired for each volunteer beginning immediately after injection and at 1-2, 3-4, 6-8, and 20-24 h after injection. Venous blood samples (0 h predose through 28 h after dosing) and 28-h cumulative urine samples were taken from each volunteer for pharmacokinetic analysis. Radiation dose estimates were performed for all volunteers, with "reference adult" (for men) and "adult female" (for women) phantoms, and both the International Commission on Radiological Protection 30 gastrointestinal tract model and the dynamic bladder model, using the MIRDOSE3 program. Two sets of estimates, 1 using a pharmacokinetic analysis of total serum radioactivity and 1 based on scintigraphic image data, were obtained for each volunteer after 123I-IAZA administration. RESULTS: Two compartments were discernible by pharmacokinetic analysis, and 4 compartments were discernible by image analysis. The urinary bladder wall received the greatest radiation dose (6.3E-02 +/- 8.7E-03 mGy/MBq), followed by the upper large intestinal wall (5.6E-02 +/- 1.2E-02 mGy/MBq), the lower large intestinal wall (5.0E-02 +/- 1.2E-02 mGy/MBq), and the thyroid (4.4E-02 +/- 1.4E-02 mGy/MBq). Approximately 90% of physiologically eliminated radioactivity was excreted through the kidneys. Radioactivity entering the intestinal tract from the gallbladder constituted <10% of biologically eliminated activity. CONCLUSION: The dosimetric analysis of 123I-IAZA in 6 healthy volunteers indicated that both disposition kinetics and radiation dosimetry support its clinical use for imaging tissue hypoxia.
Assuntos
Radioisótopos do Iodo/farmacocinética , Nitroimidazóis/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Feminino , Câmaras gama , Humanos , Hipóxia/diagnóstico por imagem , Masculino , Radiometria , Cintilografia , Distribuição TecidualRESUMO
The new FDA Guidance for Industry BA and BE Studies for Orally Administered Drug Products--General Considerations and Average, Population, and Individual Approaches to Establishing Bioequivalence imply significant changes in the areas of enrollment, cost, ethics, time, entry, validation applications (EVAs), and statistical and pharmacokinetic methods. The changes from three-period to two-period design for food effect studies, the elimination of most steady state studies, and the analyses of only the active moiety or ingredient are welcome. However, if the current guidances are adopted, additional time will be needed for participants, and more participants will be needed, resulting in higher costs to drug developers. The PK parameters needed to assess BE and the need for replicate designs for drugs with long t1/2 are still unclear. Finally, the advantages of the aggregate property of the FDA metric versus the disaggregate criteria are challenged, and four bioequivalence criteria are proposed.
Assuntos
Serviços Contratados/organização & administração , Avaliação de Medicamentos/normas , Farmacocinética , United States Food and Drug Administration/legislação & jurisprudência , Administração Oral , Interpretação Estatística de Dados , Avaliação de Medicamentos/economia , Avaliação de Medicamentos/legislação & jurisprudência , Avaliação de Medicamentos/métodos , Indústria Farmacêutica , Humanos , Projetos de Pesquisa , Fatores de Tempo , Estados UnidosRESUMO
Effects of methoxyflurane anesthesia on the pharmacokinetics of intravenous 125I-IAZA in rats are reported. No significant differences in t(1/2alpha), t(1/2beta), V(SS), and ClTB for total radioactivity (125I-IAZA and metabolites) were observed between the anesthetized (Group 1, n = 4) and nonanesthetized (Group 2, n = 3) animals. For 125I-IAZA, ClTB increased from 646 +/- 52 mL/h/kg to 2250 +/- 351 mL/h/kg and t(1/2beta) decreased from 97.7 +/- 17.5 min to 35.6 +/- 5.4 min, for Groups 1 and 2, respectively. There were no differences in V(SS) or t(1/2alpha) between the two groups. These findings support literature reports of anesthetic effects on xenobiotic pharmacokinetics, and indicate a need for caution in the evaluation of preclinical imaging studies in which animals are immobilized with anesthetics.
Assuntos
Anestesia por Inalação , Anestésicos Inalatórios/farmacologia , Metoxiflurano/farmacologia , Nitroimidazóis/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Animais , Área Sob a Curva , Biotransformação , Calibragem , Cromatografia Líquida de Alta Pressão , Meia-Vida , Radioisótopos do Iodo , Marcação por Isótopo , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Pharmacokinetic and dosimetric parameters of the hypoxic tissue imaging agent iodoazomycin arabinoside (123I-IAZA) have been investigated in human volunteers. In conjunction with this study it was necessary to develop an assay for low levels of the radiolabelled compound in blood and urine. A combination of high-performance liquid chromatography (HPLC) and gamma counting produced a highly selective, sensitive and rapid assay for the analysis of 123/125I-IAZA in human and animal blood and urine samples. Conventional HPLC assays for the tracer quantities of this radioactive agent in blood have not been reported previously. The addition of non-radiolabelled IAZA to the blood and urine samples containing radiolabelled IAZA allowed the pharmaceutical to serve as its own internal standard. This reverse isotope dilution approach permitted identification of the appropriate HPLC peak by UV detection, followed by highly sensitive quantification of the radiolabelled species by gamma counting. Blood samples were prepared for HPLC by a solid-phase extraction without the loss of IAZA from serum, with an extraction efficiency of 99.7 +/- 7.1% from human serum. Urine samples could be analyzed directly by HPLC, without the solid-phase extraction step. The detection limit in biological fluids depends on the specific activity of radiolabelled 123/125I-IAZA. In this study it was possible to detect serum concentrations of 123I-IAZA as low as 7.46 pg (21 fmol) per ml. The radiometric detection limit for 123I-IAZA in this assay was 10.8 Bq ml-1 of serum.
Assuntos
Hipóxia Celular/fisiologia , Nitroimidazóis/análise , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/urina , Calibragem , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Radioisótopos do Iodo , Nitroimidazóis/sangue , Nitroimidazóis/urina , Padrões de Referência , Espectrofotometria UltravioletaRESUMO
123I-labelled iodoazomycin arabinoside (123I-IAZA) is an experimental radiopharmaceutical that has been shown to have clinical utility for imaging regional tissue hypoxia. We report the clinical pharmacokinetics of IAZA, the radiopharmacokinetics of 123I-IAZA and total radioactivity kinetics after injection of 123I-IAZA. Six healthy volunteers each received an intravenous bolus injection of 185 MBq of 123I-IAZA. Thirteen blood samples and a cumulative urine sample were collected over 28 h from each subject. A two-compartment open model best described the disposition characteristics of all three chemical components, with terminal phase half-lives of 179 +/- 24, 232 +/- 41 and 294 +/- 27 min for 123I-IAZA, IAZA and total radioactivity, respectively. 123I-IAZA had a steady-state volume of distribution (Vss) of 0.716 +/- 0.088 l.kg-1 and a systemic clearance (Cls) of 239 +/- 48 ml.min-1. Radioactive decay was responsible for about 37% of clearance; of the remaining radioactivity, about 92% was eliminated renally. Only about 12% of 123I-IAZA was eliminated unchanged in urine, indicating that renal excretion was the major route of elimination for the radioactive metabolites rather than for 123I-IAZA itself. The effective half-lives of 123I-IAZA and total radioactivity reported here are considerably shorter than previously estimated. Our results confirm that 123I-IAZA has appropriate pharmacokinetic and radiopharmacokinetic properties to support clinical hypoxia imaging.
Assuntos
Radioisótopos do Iodo/farmacocinética , Nitroimidazóis/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Feminino , Meia-Vida , Humanos , Hipóxia/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Cintilografia , Distribuição TecidualRESUMO
Although hypoxia has been known for decades to play an important role in the outcome of radiotherapy in oncology, and inspite of the contribution of hypoxia to a myriad of pathologies that involve vascular disease, the selective imaging of hypoxic tissue has attained prominence only within the past decade. Contemporary research in the hypoxia imaging field is based largely on radiosensitizer research of the 1960's and 1970's. Early sensitizer research identified a family of nitro-organic compounds, the N-1 substituted 2-nitroimidazoles as candidate drugs. The early champion, and still the reference standard for therapeutic radiosensitization of hypoxic tumor cells is misonidazole (MISO). Its peripheral neurotoxicity led to failure in clinical studies, but its biological, biophysical and biochemical properties have been investigated in detail and serve as a basis for further design, not only of sensitizers, but of diagnostic radiopharmaceuticals for imaging tissue hypoxia. Pharmacokinetic characterization of radiopharmaceuticals, specifically radiopharmaceuticals for imaging tissue hypoxia, has not been a central theme in their development. The advent of PET, through which quantitative determinations first became possible, opened the field for both descriptive and analytical radiopharmacokinetic studies. In SPECT, however, this approach is still undergoing refinement. This paper addresses some of the underlying issues in radiopharmaceutical pharmacokinetics. There is a paucity of published radiopharmacokinetic data for SPECT hypoxia imaging agents. Consequently, the pharmacokinetic issues for MISO are presented as a basis for development of pharmacokinetics for the chemically-related imaging agents. Properties of an hypoxia marker are described from a pharmacokinetic viewpoint, a theoretical model for descriptive pharmacokinetics is introduced and finally, recent pharmacokinetic studies from our laboratory are described.
Assuntos
Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Hipóxia Celular , Humanos , Radioisótopos do Iodo , Misonidazol/análogos & derivados , Misonidazol/farmacocinética , Nitroimidazóis/farmacocinética , Radiossensibilizantes/farmacocinética , TecnécioRESUMO
Colesevelam hydrochloride (colesevelam) is a novel, potent, bile acid-binding agent that has been shown to lower LDL cholesterol a mean of 19% at a dose of 3.8 g/d. We studied the pharmacokinetics of colesevelam coadministered with six drugs: digoxin and warfarin, agents with narrow therapeutic indices; sustained-release verapamil and metoprolol; quinidine, an antiarrhythmic with a narrow therapeutic index; and valproic acid, an antiseizure medication. Six individual studies were single-dose, crossover, with or without a 4.5-g dose of colesevelam. Plasma levels were determined using validated analytical methods. Values for the ratio of ln[AUC(0-t)] with and without colesevelam were 107% for quinidine, 102% for valproic acid, 89% for digoxin, 102% for warfarin, 82% for verapamil, and 112% for metoprolol. Values for the ratio of ln[Cmax] with and without colesevelam were 107% for quinidine, 92% for valproic acid, 96% for digoxin, 99% for warfarin, 69% for verapamil, and 112% for metoprolol. The 90% confidence intervals for these ratios and for values of ln[AUC(0-inf)] that could be determined were within the 80-125% range, with the exception of verapamil. In this study, verapamil had great interindividual variability, with a 28-fold range in Cmax and an 11-fold range in AUC(0-t). In summary, pharmacokinetic studies with colesevelam did not show clinically significant effects on absorption of six other coadministered drugs.