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Horikawa, Masato; Kato, Yukio; Sugiyama, Yuichi

doi:10.1023/a:1020358910490

Cited by 66 publications

(16 citation statements)

References 19 publications

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“…Since probenecid is a potent inhibitor for MRP2/Mrp2 transporters, it is expected that co-administration of probenecid would reduce the irinotecan-induced intestinal toxicity by inhibiting the biliary excretion of SN-38. As expected, a kinetic study with rats revealed that probenecid not only markedly reduced the biliary excretion of SN-38, but also significantly decreased the irinotecan-induced intestinal toxicity [90].…”

Section: Liversupporting

confidence: 79%

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Lin¹

2006

CDM

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With few exceptions, drugs exert their effects not within the plasma compartment, but in the defined target tissues. The process of drug distribution to the active site constitutes the "link-bridge" of the pharmacokinetic/pharmacodynamic (PK/PD) relationship. In spite of the importance of drug distribution as a key factor in determining pharmacologic response, research on drug distribution has historically received much less attention than that of absorption, metabolism, and excretion. The negligence of research on drug distribution is due mainly to the inaccessibility of the target tissues for obvious ethical reasons. In addition, lack of reliable experimental tools to assess the distribution process is also a major contributing factor. Because of this negligence, drug distribution has been referred to as "the forgotten relative in clinical pharmacokinetics." Although recent advances in molecular biology have led to the identification of many drug transporters, many of the processes of drug distribution are still not fully understood. The primary aim of this article is to provide new insight into the mechanisms of drug distribution, with an attempt to describe the relationship between the drug distribution and pharmacologic response. In addition, the factors that affect the processes of drug distribution will also be reviewed. Also, validity of some key assumptions that are used to relate the processes of tissue distribution with pharmacologic activity will be discussed.

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Section: Liversupporting

confidence: 79%

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Lin¹

2006

CDM

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“…In rat, when probenecid was coadministered with CPT-11, the biliary excretion of SN-38 glucuronide decreased about 50%, whereas a slight increase in plasma concentration of SN-38 glucuronide was observed (103). Bilirubin-glucuronides are known as endogenous substrates for MRP2 and MRP3.…”

Section: The Impact Of Transporters On Pharmacokinetics Of the Glumentioning

confidence: 99%

Challenges and Opportunities with Predicting In Vivo Phase II Metabolism via Glucuronidation From In Vitro Data

2016

Curr Pharmacol Rep

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Glucuronidation is the most important phase II metabolic pathway which is responsible for the clearance of many endogenous and exogenous compounds. To better understand the elimination process for compounds undergoing glucuronidation and identify compounds with desirable in vivo pharmacokinetic properties, many efforts have been made to predict in vivo glucuronidation using in vitro data. In this article, we reviewed typical approaches used in previous predictions. The problems and challenges in prediction of glucuronidation were discussed. Besides that different incubation conditions can affect the prediction accuracy, other factors including efflux / uptake transporters, enterohepatic recycling, and deglucuronidation reactions also contribute to the disposition of glucuronides and make the prediction more difficult. PBPK modeling, which can describe more complicated process in vivo, is a promising prediction strategy which may greatly improve the prediction of glucuronidation and potential DDIs involving glucuronidation. Based on previous studies, we proposed a transport-glucuronidation classification system, which was built based on the kinetics of both glucuronidation and transport of the glucuronide. This system could be a very useful tool to achieve better in vivo predictions.

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“…Under this condition, CPT-11-induced watery diarrhea, changes in intestinal marker enzymes and body weight reduction were much less in the probenecid-treated group, although the degree of bone marrow suppression was almost the same as In addition, it is found that the mucosal damage caused by CPT-11 treatment including a decrease of the villi/crypt ratio, an increase of apoptotic cells, as well as an increase that in the control. Co-administration of probenecid with a reduced dose of CPT-11 potently reduced SN-38 exposure in gastrointestinal tissues and alleviated CPT-11-induced late-onset toxicity [186]. an antineoplastic agent [189].…”

Section: Inhibitors Of Drug Transportermentioning

confidence: 99%

Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea

Yang¹,

Chan³

et al. 2005

CMC

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Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.

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Abstract: Coadministration of probenecid with a reduced dose of CPT-11 potently reduces both SN-38 exposure and CPT-11-induced late-onset toxicity in gastrointestinal tissues, possibly by inhibiting the biliary excretion of CPT-11 and/or its metabolites.

Cited by 66 publications

References 19 publications

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Challenges and Opportunities with Predicting In Vivo Phase II Metabolism via Glucuronidation From In Vitro Data

Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea

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