O citalopram (CITA), inibidor seletivo da recaptação da serotonina, é disponível na clínica como mistura racêmica dos enantiômeros (+)-(S) e (-)-(R) ou como enantiômero puro (+)-(S)-CITA. O CITA é metabolizado pelo CYP2C19, CYP2D6 e CYP3A ao desmetilcitalopram (DCITA) e pelo CYP2D6 ao didesmetilcitalopram. O estudo investiga a influência de inibidores enzimáticos no metabolismo enantiosseletivo do CITA em ratos e em voluntários sadios. Os ratos machos Wistar (n=6 para cada grupo) foram tratados com dose única de 20 mg/Kg de CITA (grupo controle) ou pré-tratados com 80 mg/Kg de quinidina (grupo quinidina), 10 mg/Kg de fluvoxamina (grupo fluvoxamina) ou 50 mg/Kg de cetoconazol (grupo cetoconazol). As amostras de sangue foram colhidas dos ratos até 20 h após a administração do CITA. Os voluntários sadios fenotipados como metabolizadores extensivos (EM) do CYP2C19 (omeprazol como fármaco marcador), EM do CYP2D6 (debrisoquina como fármaco marcador) e com atividade normal do CYP3A (midazolam como fármaco marcador) receberam dose única p.o. de 20 mg de CITA racêmico associado ou não ao omeprazol (20 mg/dia durante 18 dias). Os enantiômeros do CITA e do DCITA foram analisados no sistema LC-MS/MS, com a coluna quiral Chiralcel OD-R e fase móvel constituída por acetonitrila:metanol:água (30:30:40 v/v/v) contendo 0,05 % de dietilamina. O método foi linear no intervalo de concentrações de 0,1 20 ng de cada enantiômero do CITA e DCITA/mL de plasma humano e de de 0,1 500 ng de cada enantiômero do CITA e DCITA/mL de plasma de rato. Os coeficientes de variação obtidos nos estudos da precisão e a inexatidão foram inferiores a 15 % para plasma humano e plasma de ratos. A disposição cinética do CITA é enantiosseletiva nos ratos dos grupos controle (razão de AUCS/R de 0,4), quinidina (razão de AUCS/R de 0,5) e cetoconazol (razão de AUCS/R de 0,8). A inibição do CYP2D pela quinidina resultou em inibição do metabolismo do CITA e do DCITA de maneira não enantiosseletiva. A inibição do CYP2C pela fluvoxamina e do CYP3A pelo cetoconazol resultou em inibição somente do metabolismo do (+)-(S)-CITA. A disposição cinética do CITA em voluntários sadios é enantiosseletiva na ausência de tratamento com o omeprazol com observação de maior proporção plasmática do enantiômero (-)-(R)-CITA. A razão de AUCS/R obtida para o CITA foi de 0,56 e para o metabólito DCITA foi de 1,06. A administração de CITA racêmico a voluntários sadios em tratamento com o omeprazol exibe perda da enantiosseletividade na farmacocinética do CITA. A razão de AUCS/R foi de 0,96 para o CITA e de 0,92 para o DCITA. A administração de omeprazol em doses múltiplas a voluntários sadios inibe de maneira enantiosseletiva o metabolismo do eutômero (+)-(S)-CITA com aumento das concentrações plasmáticas em aproximadamente 140%. / Citalopram (CITA), a selective serotonin reuptake inhibitor, is available for clinical use as a racemic mixture of the (+)-(S) and (-)-(R) enantiomers or as the pure (+)-(S)-CITA enantiomer. CITA is metabolized by CYP2C19, CYP2D6 and CYP3A to demethylcitalopram (DCITA) and by CYP2D6 to didemethylcitalopram. The present study investigated the influence of enzyme inhibitors on the enantioselective metabolism of CITA in rats and healthy volunteers. Male Wistar rats (n=6 for each group) received a single dose of 20 mg/kg CITA (control group) or were pretreated with 80 mg/kg quinidine (quinidine group), 10 mg/kg fluvoxamine (fluvoxamine group), or 50 mg/kg ketoconazole (ketoconazole group). Blood samples were collected from the animals up to 20 h after the administration of CITA. Healthy volunteers phenotyped as extensive metabolizers of CYP2C19 (omeprazole as marker drug) and of CYP2D6 (debrisoquine as marker drug) and those with normal CYP3A activity (midazolam as marker drug) received a single oral dose of 20 mg racemic CITA combined or not with omeprazole (20 mg/day for 18 days). The CITA and DCITA enantiomers were analyzed by LC-MS/MS using a Chiralcel OD-R chiral column and a mobile phase of acetonitrile:methanol:water (30:30:40, v/v/v) containing 0.05% diethylamine. The method was linear in the concentration range of 0.1-20 ng of each CITA and DCITA enantiomer/mL human plasma and of 0.1-500 ng of each CITA and DCITA enantiomer/mL rat plasma. Accuracy and precision were below the acceptance limits of 15% for human and rat plasma. The kinetic disposition of CITA was enantioselective in rats of the control (AUCS/R ratio = 0.4), quinidine (AUCS/R ratio = 0.5) and ketoconazole (AUCS/R ratio = 0.8) groups. The inhibition of CYP2D by quinidine resulted in the non-enantioselective inhibition of the metabolism of CITA and DCITA. The inhibition of CYP2C by fluvoxamine and of CYP3A by ketoconazole only inhibited the metabolism of (+)-(S)-CITA. The kinetic disposition of CITA in healthy volunteers was enantioselective in the absence of treatment with omeprazole, with the observation of a higher plasma proportion of the (-)-(R)-CITA enantiomer. The AUCS/R ratio was 0.56 for CITA and 1.06 for the DCITA metabolite. The administration of racemic CITA to healthy volunteers treated with omeprazole showed a loss of enantioselectivity in the pharmacokinetics of CITA. The AUCS/R ratio was 0.96 for CITA and 0.92 for DCITA. The administration of multiple doses of omeprazole to healthy volunteers enantioselectively inhibited the metabolism of the (+)-(S)-CITA eutomer, with an approximately 140% increase of plasma concentrations

Submitted by Biblioteca da Faculdade de Farmácia (bff@ndc.uff.br) on 2017-03-27T17:31:49Z No. of bitstreams: 1 Malhado ,Mayara [Dissertação, 2015].pdf: 1482168 bytes, checksum: b9d24e08c80ca59631903c4bbe1af945 (MD5) / Made available in DSpace on 2017-03-27T17:31:49Z (GMT). No. of bitstreams: 1 Malhado ,Mayara [Dissertação, 2015].pdf: 1482168 bytes, checksum: b9d24e08c80ca59631903c4bbe1af945 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Praziquantel (PZQ) é o fármaco recomendado pela Organização Mundial de Saúde para o tratamento da esquistossomose. No Brasil é comercializado apenas sob a forma de comprimido, o que complica o tratamento de crianças tanto devido à dificuldade de adequação da dose, como pelo sabor extremamente amargo. Nesse sentido, Nanopartículas de Poli (Metil Metacrilato) contendo PZQ (PMMA-PZQ) foram desenvolvidas pelo grupo de pesquisa do Laboratório de Engenharia de Polimerização da COPPE-UFRJ, visando a elaboração de suspensão de PZQ. O presente estudo objetivou avaliar o perfil farmacocinético de PZQ administrado em nanopartículas (PZQ-NP) e compará-lo ao perfil farmacocinético de PZQ administrado na forma livre (PZQ-L), como fase pré-clínica do desenvolvimento de nova formulação farmacêutica. Foram utilizados ratos Wistar, fêmeas, com peso entre 200 e 300 g. O sangue foi coletado nos tempos 0, 5 min, 10 min, 15 min, 20 min, 30 min, 1 h, 1:30 h, 2 h, 4 h, 8 h, 10 h, 12 h e 24 h após a administração por via oral, em dose única, de 60 mg/ kg de PZQ suspendido em 1 mL de água com 2% de Cremophor® (grupos PZQ-NP e PZQ-L) ou 1 mL de veículo (grupo controle). A manipulação e os procedimentos com os animais foram aprovados pela Comissão de Ética no Uso de Animais da Universidade Federal Fluminense. O PZQ foi extraído do plasma utilizando extração líquido-líquido com terc-butil-metil éter. O diazepam foi utilizado como padrão interno e a análise das amostras foi realizada por Cromatografia Líquida de Alta Eficiência acomplada a Espectrometria de Massas. Os valores obtidos para Concentração máxima (Cmáx) e Área Sob a Curva (ASC0-t e ASC0-∞) do grupo PZQ-NP foram aproximadamente 3 vezes menor comparado ao grupo PZQ-L. No entanto, o tempo para atingir a concentração máxima (Tmáx), a constante de eliminação (Ke) e o tempo de meia vida de eliminação (T 1/2β) não apresentaram valores estatísticamente diferentes. Estes resultados sugerem que a absorção é possivelmente a etapa limitante para obtenção de melhores parâmetros farmacocinéticos de PZQ adminstrado em nanopartículas de PMMA. Assim, são necessários mais estudos visando a compreensão dos mecanismos de absorção das nanopartículas de PMMA-PZQ e do processo de liberação do fármaco a partir matriz polimérica in vivo para que o nanosistema seja aprimorado e o produto disponibilizado para uso clínico / Praziquantel (PZQ) is the drug recommended by the World Health Organization for the treatment of schistosomiasis. In Brazil it is comercialised only in tablet, which complicates the treatment of children because of the difficulty of adapting the dose , and its extremely bitter taste. In this way, PZQ loaded in Poly(methyl methacrylate) Nanoparticle (PMMA-NP) were developed at Laboratório de Engenharia de Polimerização (COPPE –UFRJ), in order to develop PZQ suspension. This study aimed to evaluate the pharmacokinetic profile of PZQ loaded in nanoparticles ( PZQ -NP ) and compare it to the pharmacokinetic profile of PZQ administered in free form ( PZQ -L ) , as pre- clinical phase of the new pharmaceutical formulation development. Wistar rats, femeles, weighing nearby 300 g were used, was the experimental model employed. Blood was collected at 0, 5 min, 10 min , 15 min, 20 min, 30 min , 1 h 1:30 h , 2 h , 4 h, 8 h , 10 h , 12 h and 24 h after orally administration at a single dose of 60 mg / kg PZQ suspended in 1 ml of water containing 2% Cremophor® ( NP - PZQ groups and PZQ -L) or 1 ml of vehicle (control group). The handling and procedures with animals were approved by the Ethics Committee on Animal Use of Universidade Federal Fluminense. PZQ was extracted from plasma by liquid-liquid extraction with terc-butyl methyl ether. Diazepam was used as internal standard and the analysis of samples was performed by High Performance Liquid Chromatography Efficiency tandem Mass Spectrometry. The values obtained for Maximum Concentration (Cmax) and Area Under Curve (ASC0-t and ASC0 0-∞ ) for group PZQ-NP were about 3 times lower compared to PZQ-L group . However , the time for achieving maximum concentration ( Tmax ), the elimination constant (Ke) and the half-life time of elimination (T 1/2β) were not statistically different. These results suggest that the absorption is probably the rate-limiting step for obtaining better pharmacokinetic parameters of PZQ administrated on PMMA nanoparticles. Thus, further studies are needed to understand both the PMMA – PZQ absorption mechanisms, as the process of drug release through polymer matrix in vivo, in order to enhanced the nanosystem and then the product to become available for clinical use

Le traitement actuel de la tuberculose chimio-sensible est de 6 mois, ce qui est beaucoup trop long et entraine des défauts d’adhésion au traitement, des échecs thérapeutiques par sélection de bactéries résistantes. Puisque dans le futur proche, aucun nouveau traitement ne permettra de raccourcir la durée de traitement, d’autres voies doivent être recherchées, entre autres l’augmentation de la posologie de rifampicine (R) au-delà des 10 mg/kg actuellement recommandés qui pourrait permettre un traitement de 3-4 mois.Notre travail, réalisé dans le cadre d’essais cliniques, a consisté d’une part à étudier la tolérance d’une dose élevée de R au sein du traitement antituberculeux standard chez des patients tuberculeux séronégatifs ou séropositifs pour le VIH, et d’autre part l’interaction entre une double dose de R (20mg/kg) et le traitement antirétroviral, en particulier l’efavirenz (EFV). Enfin un autre axe de recherche a consisté à étudier si la négativation des cultures de crachat à 2 mois pouvait être un marqueur de l’efficacité du traitement antituberculeux dans les essais cliniques. Afin de répondre à ces objectifs, les études suivantes ont été réalisées.Une étude ouverte, de Phase II, randomisée, contrôlée (RIFATOX) a été mise en place (Bolivie, Pérou and Ouganda). Trois cent patients tuberculeux, séronégatifs pour le VIH ont été randomisés entre 3 schémas thérapeutiques se différenciant par la posologie de la R durant les 16 premières semaines : R à 10, 15 ou 20 mg/kg. La fonction hépatique et la réponse bactériologiques ont été monitorées. La toxicité hépatique n’était pas plus importante à dose élevée de R. En utilisant les résultats des patients ougandais, nous avons montré que la négativation des cultures à deux mois était influencée par le type de milieu de culture utilisé, avec négativation plus importante en milieu solide qu’en milieu liquide pour les traitements avec dose élevée de R. Ces résultats nous amènent à recommander que le même milieu de culture soit utilisé dans tous les sites lors d’essais multicentriques visant à étudier l’efficacité de traitement antituberculeux.Une étude bibliographique « systématique » a été réalisée afin de colliger les informations existantes sur l’efficacité, la tolérance et les interactions pharmacocinétiques de l’EFV associé au traitement antituberculeux à posologie standard dans les pays à forte endémie. Vingt-deux articles publiés entre 2006 et 2016 ont été sélectionnés. Aucune relation entre des concentrations élevées d’EFV et la survenue d’effets indésirables neurologiques ou hépatiques n’a pu être mise en évidence.Au vu de ces informations, un essai pharmacocinétique de phase 2, ouvert (ANRS12292 RIFAVIRENZ trial) a randomisé 97 patients tuberculeux vivant avec le VIH et naïfs de traitement antirétroviral entre 3 bras de traitement : R20mg/kg+EFV 600mg, R20mg/kg +EFV 800 mg et R10mg/kg+EFV600mg (bras contrôle). R était associé au traitement antituberculeux à posologie standard et EFV associé à deux analogues nucléosidiques (tenofovir+lamivudine) a été initié 2-4 semaines après le traitement antituberculeux. Après 8 semaines de suivi, tous les patients ont reçu les traitements à posologie standard. Des prélèvements sanguins ont été réalisés pour étudier la pharmacocinétique de l’EFV associé à R ou administré seul (4 semaines après arrêt du traitement antituberculeux). Malgré une légère diminution des concentrations d’EFV dans le bras R20 mg/kg+EFV 600mg, les concentrations sont restées dans la zone des concentrations thérapeutiques. Quelque soit le bras de traitement, le traitement a été bien toléré. Cependant s’il n’y avait pas de différence sur l’efficacité virologique mesurée à 12 semaines, elle était diminuée à 24 semaines dans le bras R20 mg/kg+EFV 600mg. La pertinence clinique de ce résultat est en cours d’évaluation pour que des patients tuberculeux vivant avec le VIH puissent être inclus dans de futurs essais de phase 3. / The recommended 6-month treatment for drug-susceptible tuberculosis (DS-TB) is too long, hence threatening patient adherence, with resulting treatment failure and drug-resistance. Consequently, this complicates efforts towards achieving the TB control and elimination goal. Currently, no new drug is expected in the short term for reducing treatment duration. We hypothesized that optimization of the current treatment regimen with use of high-dose rifampicin (R), above the 10mg/kg current dose, might result in a shorter TB treatment duration (3-4 months). Clinical trials were conducted to investigate two research areas: first, Safety of high-dose R in HIV-negative TB and in HIV-TB coinfected patients; secondly, drug-drug interaction between high-dose R and antiretroviral drugs. A 3rd research area addressed the use of 2 months sputum culture conversion as surrogate marker for treatment efficacy in TB trials.A Phase II, open-label randomized controlled trial (RIFATOX) was conducted with sites in Bolivia, Peru and Uganda. Three hundred HIV-negative smear-positive TB patients were randomised between three regimens differing only by R dose during the first 16 weeks of the standard 24 weeks treatment: R at 10 mg/kg and two high-R doses (15mg/kg or 20mg/kg). Liver function and bacteriological response were monitored. There was no significant increase in hepatotoxicity with high-dose R. Using data from the cohort of patients from the Ugandan site only, we showed that month-2 culture conversion, a commonly used surrogate marker in phase 2 trials was influenced by the culture method used with significantly higher conversion rates noted with solid versus liquid media within patients on high-R dose regimens. We therefore recommend use the same culture method across sites within multi-centric TB trials.We conducted a systematic review to gather existing information on the pharmacokinetics, adverse effects and efficacy of efavirenz (EFV), the most commonly used antiretroviral drug, co-administered with R-based TB regimens among high TB/HIV-burden countries. Twenty-two articles published between 2006 and 2016 were analyzed. With the use of 600mg EFV daily, plasma concentrations on average were above the minimum therapeutic concentrations during R co-administration with good safety and efficacy. No clear relationship between supratherapeutic EFV concentrations and occurrence of neurological and hepatic adverse events was observed.Then, we conducted a phase-2, randomized, open-label pharmacokinetic trial (ANRS12292 RIFAVIRENZ trial) among 97 DS-TB patients and antiretroviral therapy (ART)-naïve Ugandan patients. These were randomized between 3 drug regimens: 2 using R (20mg/Kg) with ART initiation 2-4 weeks later with EFV600mg/day or 800mg/day) and a control regimen using R10mg/kg and EFV600mg/day. At 8 weeks, all patients were switched to standard R and EFV doses. All patients had intensive pharmacokinetic sampling 4 weeks after EFV-R co-administration, and 4 weeks after R discontinuation. Despite a trend of lower EFV concentration when the R dose was doubled, concentrations remained within the therapeutic window. Treatment with high-dose R was well tolerated. Virological efficacy was high during the first 12 weeks on ART but reduced in the R arms after 24 weeks. We conclude that, use of high-dose R at 20mg/Kg is safe and could be evaluated in larger trials towards shortening of treatment for DS-TB patients. Due to late virological failures in patients on R 20 mg/kg and standard EFV dose, comprehensive efforts through additional research are needed to fast-track the inclusion of TB-HIV co-infected patients in phase 3 trials.

Class of 2014 Abstract / Specific Aims: Busulfan is a chemotherapy used in conditioning regimens for hematopoeitic stem cell transplant (HSCT) that requires therapeutic drug monitoring (TDM) to reduce ther risk of adverse effects. Variable oral absorption and several studies demonstrating decreased toxicity with the intravenous formulation have led to IV preference despite the lower acquisition cost of oral busulfan. However, these studies failed to consider therapeutic drug monitoring and their results may therefore be flawed. The objective of this retrospective chart review was to determine the adverse effect, outcome profile, and cost-effectiveness of IV versus PO busulfan at a single medical center under TDM. Methods: This quality improvement project was a retrospective cohort analysis using patient data from a single large academic medical center from January 2007 to April 2013. Patients were included if they were 18 years or older and had undergone HSCT using either IV or PO busulfan using standard dosing regimens. This data was then used to design a cost-effectiveness model in order to determine if IV or PO busulfan is cost effective. Main Results: There were 68 subjects receiving autologous transplants and 37 subjects receiving allogeneic transplants that received busulfan as part of their pretreatment therapy and were included in this study. Allogeneic and autologous transplant populations were analyzed separately. In both populations there was no difference in occurrence of pulmonary toxicity, HVOD, or mucositis between the IV or PO groups. IV busulfan was significantly associated with an increased need for patient controlled analgesia in both autologous and allogeneic populations (p=0.038 and 0.028 respectively). Total cost of PO therapy was $30,081 and $30,047 less than IV for autologous and allogeneic transplants, respectively. PO therapy also represented a cost savings of $41 and $57 dollars for autologous and allogeneic transplants, respectively. This was confirmed through bootstrapping technique, which found PO to be dominant to IV busulfan. Conclusion: In conclusion, this study finds PO busulfan to be a therapeutically equivalent and cost saving option as part of a pretreatment regimen for both autologous and allogeneic hematopoietic stem cell transplants when therapeutic drug monitoring is performed.

Les rodonticides anticoagulants (AR) sont utilisés depuis les années 40 pour lutter contre les rongeurs. Seulement quelques années après leur commercialisation des cas de résistances ont été décrits. Les mécanismes à l'origine de ces résistances sont relativement bien décrits chez le rat brun et la souris domestique mais très peu chez le rat noir. Une étude de terrain a permis de mettre en évidence 8 mutations codantes du gène Vkorc1 chez le rat noir responsable d'un possible phénotype résistant. Actuellement, les résistances concernent surtout les AR de 1ère génération. Ainsi, les AR de 2nde génération qui sont encore actifs chez les rongeurs résistants sont de plus en plus utilisés. Cependant, en raison de leur longue rémanence tissulaire, ils sont responsables de phénomènes d'intoxication de la faune non cible. Face à ce problème majeur, une nouvelle génération d'anticoagulants plus écocompatible doit être développée. Ce travail propose une méthode pour le développement d'une 3ème génération d'AR en retravaillant la 2nde génération via le concept de la stéréochimie. En effet, les AR de 2nde génération sont un mélange de diastéréoisomères qu'il est possible de séparer. Les propriétés biologiques et toxicocinétiques des diastéréoisomères de chacune des molécules actuellement sur le marché ont été étudiées. Systématiquement, l'un des deux couples de diastéréoisomères est éliminé beaucoup plus rapidement que l'autre. Ainsi, le développement d'appâts enrichis avec le couple de diastéréoisomères les moins persistants, permettrait de réduire les risques écotoxicologiques associés à leur utilisation / Anticoagulant rodenticides (AR) have been used since the 1940s to control rodents. Only a few years after their commercialization, cases of resistance have been described. The mechanisms responsible for these resistances are relatively well described in brown rats and domestic mice but approximately unknown in black rats. A field study performed in France and Spain revealed 8 coding mutations of the Vkorc1 gene in black rat populations responsible for a possible resistant phenotype to 1st generation ARs essentially, as described for other rodents. 2nd generation ARs still active in resistant rodents are thus increasingly used. However, due to their long tissue persistence, their use is associated with an increased risk of secondary poisoning of wildlife. Faced to this major problem, a new generation of more ecofriendly anticoagulants must be developed. This work proposes a method for the development of a 3rd generation of AR by revisiting the 2nd generation AR based on the stereochemistry. Indeed, 2nd generation ARs are a mixture of diastereomers that can be easily separated. The biological and toxicokinetic properties of the diastereoisomers of each of the molecules currently on the market have been studied. Systematically, one of the two pairs of diastereoisomers is eliminated much faster than the other. Thus, the development of baits enriched with the pair of less persistent diastereoisomers would reduce the ecotoxicological risks associated with their use

Selected drugs are being utilized as models of putative colon carcinogens in a study of the influence of major types of dietary fiber upon drug pharmacokinetics. Adult, male Wistar rats were pretreated with standardized, isocaloric hydrated gelatin diets containing no fiber or 15% (w/w) cellulose, lignin, hemicellulose (metamucil), or pectin for 30 days. An additional group was fed lab chow ad libitum as a reference control. The pharmacokinetics of acetaminophen, FD & C Red No. 2 and mirex were examined following oral administration in three separate experiments. Among fiber types, pectin and hemicellulose (Metamucil) caused higher peak plasma concentrations of acetaminophen and faster rates of absorption. There was no effect of fiber type on the rate of acetaminophen elimination as determined by the interpretation of the plasma data using the computer programs AUTOAN2 and NONLIN69. Minimal quantities of Red No. 2 were absorbed from the rat intestinal tract, but its microbial metabolite, naphtionic acid, was readily taken up. Pectin produced a 5-fold higher peak plasma concentration of naphthionic acid than control animals on fiber free diet. Cellulose feeding lowered peak plasma concentration of naphthionic acid compared to the fiber control animals. Lack of any fiber in the diet produced a prolonged peak plasma concentration of napthionic acid. The metabolism of Red No. 2 to naphtionic acid by rat cecal contents was augmented by pectin feeding, alone among fiber types. Red No. 2 decreased intestinal transit times in all diet groups, including controls, with there being no difference in transit times between fiber-fed and control animals. Hemicellulose and pectin feeding lowered peak plasma concentrations of mirex compared to control and cellulose fed animals. Lignin, however produced higher peak plasma concentrations of mirex and a 4-fold higher rate of mirex elimination when compared to the fiber-free control group. These differential effects of specific fiber types upon the absorption and disposition of acetaminophen, Red No. 2 and mirex were not consistantly related to the chemical binding-capacities of the fibers of their water-holding capacities.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第21345号 / 薬科博第95号 / 新制||薬科||10(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 髙倉 喜信, 教授 小野 正博, 教授 山下 富義 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

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No description available.

No / Purpose: Combretastatin A4 phosphate (CA4P) and its structural analog, combretastatin A1 phosphate (CA1P), are soluble prodrugs capable of interacting with tubulin and causing rapid vascular shutdown within tumors. CA4P has completed Phase I clinical trials, but recent preclinical studies have shown that CA1P displays a greater antitumor effect than the combretastatin A4 (CA4) analog at equal doses. The aim of this study, therefore, is to compare pharmacokinetics and metabolism of the two compounds to determine whether pharmacokinetics plays a role in their differential activity. Experimental Design: NMRI mice bearing MAC29 tumors received injection with either CA4P or CA1P at a therapeutic dose of 150 mg/kg-1 , and profiles of both compounds and their metabolites analyzed by a sensitive and specific liquid chromatography/mass spectroscopy method. Results: The metabolic profile of both compounds is complex, with up to 14 metabolites being detected for combretastatin A1 (CA1) in the plasma. Many of these metabolites have been identified by liquid chromatography/mass spectroscopy. Initial studies, however, focused on the active components CA4 and CA1, where plasma and tumor areas under the curve were 18.4 and 60.1 microgram/h/ml-1 for CA4, and 10.4 and 13.1 microgram/h/ml-1 for CA1, respectively. In vitro metabolic comparisons of the two compounds strongly suggest that CA1 is metabolized to a more reactive species than the CA4. Conclusions: Although in vitro studies suggest that variable rates of tumor-specific prodrug dephosphorylation may explain these differences in pharmacokinetics profiles, the improved antitumor activity and altered pharmacokinetic profile of CA1 may be due to the formation of a more reactive metabolite.