Pharmacokinetics of Propofol and Extrahepatic UGT1A6 Gene Expression in Anhepatic Rats

Gu, Jianteng; Lü, Kun; Xia, Peiyuan; Tang, Min; Dai, Qing; Ma, Daqing; Tao, Guocai

doi:10.1159/000236523

Cited by 6 publications

(5 citation statements)

References 59 publications

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“…The UGT1A6 has also been suggested to contribute to the hepatic and extrahepatic propofol metabolism [ 61 , 83 ]. Although UGT1A9 is the main enzyme involved in the glucuronidation of propofol in humans, it does not exists in rats [ 84 , 85 ].…”

Section: Pharmacokinetics Of Propofolmentioning

confidence: 99%

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

Dinis-Oliveira

2018

BioMed Research International

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Propofol is an intravenous short-acting anesthetic widely used to induce and maintain general anesthesia and to provide procedural sedation. The potential for propofol dependency and abuse has been recognized, and several cases of accidental overdose and suicide have emerged, mostly among the health professionals. Different studies have demonstrated an unpredictable interindividual variability of propofol pharmacokinetics and pharmacodynamics with forensic and clinical adverse relevant outcomes (e.g., pronounced respiratory and cardiac depression), namely, due to polymorphisms in the UDP-glucuronosyltransferase and cytochrome P450 isoforms and drugs administered concurrently. In this work the pharmacokinetics of propofol and fospropofol with particular focus on metabolic pathways is fully reviewed. It is concluded that knowing the metabolism of propofol may lead to the development of new clues to help further toxicological and clinical interpretations and to reduce serious adverse reactions such as respiratory failure, metabolic acidosis, rhabdomyolysis, cardiac bradyarrhythmias, hypotension and myocardial failure, anaphylaxis, hypertriglyceridemia, renal failure, hepatomegaly, hepatic steatosis, acute pancreatitis, abuse, and death. Particularly, further studies aiming to characterize polymorphic enzymes involved in the metabolic pathway, the development of additional routine forensic toxicological analysis, and the relatively new field of ‘‘omics” technology, namely, metabolomics, can offer more in explaining the unpredictable interindividual variability.

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Section: Pharmacokinetics Of Propofolmentioning

confidence: 99%

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

Dinis-Oliveira

2018

BioMed Research International

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“…One‐stage hepatectomy or hepatic devascularization techniques employ a number of different strategies to avoid splanchnic congestion. Venous shunt of the splanchnic circulation can be done in different ways using, for example, Y‐shaped graft , V‐shaped polyethylene prosthesis , side‐to‐side mesentericocaval shunt or silicone catheter , whereas others simply clamp the portal vein and accept splanchnic congestion . The procedures using Y‐shaped graft and V‐shaped polyethylene prosthesis also address the problem of removal of the intrahepatic part of VCC as part of the Y‐shaped graft or V‐shaped prosthesis is used to replace its intrahepatic section.…”

Section: Hepatectomymentioning

confidence: 99%

“…Simply clamping the portal vein will inevitably cause splanchnic congestion, and consequently, this approach should only be used for experiments with a very limited time course. Clamping of the portal vein is only used for hepatic devascularization in experiments in which the intrahepatic part of the VCC is kept intact .…”

Section: Hepatectomymentioning

confidence: 99%

“…In such cases, complete or partial removal of a major excretion organ such as liver or kidneys can be helpful to shed light on the specific clearance mechanisms of the drug in question. Indeed, nephrectomy and hepatectomy have been used as models in pharmacokinetic studies to investigate clearance mechanism of many different drugs and potential drug candidates . For example, the use of a hepatectomized rat model has clearly demonstrated that the elimination of pentobarbital proceeds primarily via hepatic metabolism .…”

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confidence: 99%

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Nephrectomized and Hepatectomized Animal Models as Tools in Preclinical Pharmacokinetics

Vestergaard¹,

Agersø

Lykkesfeldt

2013

Basic Clin Pharma Tox

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Early understanding of the pharmacokinetics and metabolic patterns of new drug candidates is essential for selection of optimal candidates to move further in to the drug development process. In vitro methodologies can be used to investigate metabolic patterns, but in general, they lack several aspects of the whole-body physiology. In contrast, the complexity of intact animals does not necessarily allow individual processes to be identified. Animal models lacking a major excretion organ can be used to investigate these individual metabolic processes. Animal models of nephrectomy and hepatectomy have considerable potential as tools in preclinical pharmacokinetics to assess organs of importance for drug clearance and thereby knowledge of potential metabolic processes to manipulate to improve pharmacokinetic properties of the molecules. Detailed knowledge of anatomy and surgical techniques is crucial to successfully establish the models, and a well-balanced anaesthesia and adequate monitoring of the animals are also of major importance. An obvious drawback of animal models lacking an organ is the disruption of normal homoeostasis and the induction of dramatic and ultimately mortal systemic changes in the animals. Refining of the surgical techniques and the post-operative supportive care of the animals can increase the value of these models by minimizing the systemic changes induced, and thorough validation of nephrectomy and hepatectomy models is needed before use of such models as a tool in preclinical pharmacokinetics. The present MiniReview discusses pros and cons of the available techniques associated with establishing nephrectomy and hepatectomy models.

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“…Esses autores sugerem que a farmacocinética do propofol durante as fases pré-anepática e anepática são semelhantes e estão associadas à enzima UDPglucuronosiltransferase 1A6 (UGT1A6) tanto no metabolismo intra como extrahepático, sendo que o acúmulo de propofol na fase anepática pode ser explicado pelo fato dessa via metabólica estar limitada e também pela oclusão do hilo hepático (Gu et al, 2009). Estudo em porcos também verificaram estabilidade nos valores plasmáticos do propofol entre as fases pré-anepática e anepática, sugerindo que o metabolismo extra-hepático desse fármaco mantém as concentrações plasmáticas relativamente estáveis (Murayama et al, 2005).…”

Section: Atributos Principais Para Atender a Finalidade Da Pesquisaunclassified

Transplante hepático

Soeiro¹

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convivência proveitosa para o meu aprendizado e pelo grande auxílio no meu crescimento científico. Á Profa. Dra. Lídia Raquel de Carvalho do Departamento de Estatística do Instituto de Biociências de Botucatu -UNESP, meu agradecimento pelo auxílio na análise estatística e ensinamentos.Ao Dr. Cássio Neves Ferreira, sócio e amigo, que sempre colaborou, possibilitando minha frequência no programa de pós-graduação. Aos funcionários do Departamento de Anestesiologia daFaculdade de Medicina de Botucatu -UNESP, Sra. Joana, Sra. Sônia e Sra.Neli, pela amizade e atenção que sempre me dispensaram.Á diretoria da Unimed de Sorocaba e do Hospital Unimed de Sorocaba, pela anuência para a realização dos transplantes.. LISTA DE FIGURAS RESUMOO objetivo do estudo foi analisar a experiência de um único centro com duas técnicas de transplante de fígado (TOF), convencional (C) e piggyback (PB), e comparar o intra e pós-operatórios, o custo financeiro e a sobrevivência do receptor e enxerto. Uma série consecutiva (2003)(2004)(2005)(2006) de 60 TOF em adultos foi analisada, sendo 29 no grupo PB e 31 no grupo C. Não houve diferença entre o perfil dos doadores dos grupos C e PB, mas 73% dos enxertos foram provenientes de doadores com fígados "marginais". Todos os pacientes foram submetidos à anestesia venosa total com propofol, remifentanil e cisatracúrio. A sobrevivência dos enxertos foi semelhante nos grupos em um, três e cinco anos (p > 0.05). No grupo C, foram realizados 4 retransplantes e nenhum no grupo PB. A evolução da função renal e hepática no pós-operatório foi semelhante, exceto no 1º e 5º dia do pós-operatório, quando os valores da creatinina plasmática foram maiores no grupo C (p < 0,05). A partir da fase anepática até o término da cirurgia, a pressão venosa central foi menor e a frequência cardíaca maior no grupo C (p < 0,05). A pressão de artéria pulmonar foi menor na fase anepática no grupo C ( p< 0,05). Não houve diferença de débito cardíaco e pressão de artéria pulmonar ocluída entre os grupos (p > 0,05). O tempo de cirurgia, anestesia e fase anepática foi maior no grupo PB (p < 0,05), mas não o tempo de isquemia fria e quente (p > 0,05). Houve maior utilização de concentrado de hemácias no grupo PB durante o intraoperatório (p < 0,05). A maioria dos pacientes, nos dois grupos, teve desintubação traqueal na sala de operação. Não houve diferença entre os grupos no tempo de permanência no hospital e na UTI e nos custos (p >0,05). Concluímos que, no período intraoperatório, a técnica piggyback, em relação à técnica convencional, tem menor alteração hemodinâmica, maior duração e utiliza mais concentrados de hemácias e, no período pós-operatório, a evolução clínica, a sobrevida dos pacientes e enxertos e os custos financeiros dos transplantes são semelhantes. ABSTRACT

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Pharmacokinetics of Propofol and Extrahepatic UGT1A6 Gene Expression in Anhepatic Rats

Cited by 6 publications

References 59 publications

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

Nephrectomized and Hepatectomized Animal Models as Tools in Preclinical Pharmacokinetics

Transplante hepático

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