Drug metabolising activity of freshly isolated human hepatocytes.

Tee, Lisa; Seddon, Tom; Boobis, AR; Davies, DS

doi:10.1111/j.1365-2125.1985.tb02645.x

Cited by 33 publications

(4 citation statements)

References 20 publications

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“…Hepatocytes exhibit less complexity than the intact organ while retaining important liver-specific cellular functions that may be lacking in other in vitro systems (i.e., plasma membrane vesicles; transport proteins transfected in nonmammalian cells) and may be used to examine specific transport functions at the membrane level. Hepatocytes isolated from human liver tissue avoid potential issues with respect to species differences in hepatobiliary disposition (79,80). Isolated hepatocytes have been used extensively to investigate hepatic uptake mechanisms, although redistribution of canalicular membrane proteins and loss of cell polarity limit the utility of freshly isolated hepatocytes for studying drug excretion (81).…”

Section: Model Systems For Hepatobiliary Drug Transportmentioning

confidence: 99%

The Complexities of Hepatic Drug Transport: Current Knowledge and Emerging Concepts

Chandra

Brouwer²

2004

Pharm Res

251

169

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Recently, hepatic transport processes have been recognized as important determinants of drug disposition. Therefore, it is not surprising that characterization of the hepatic transport and biliary excretion properties of potential drug candidates is an important part of the drug development process. Such information also is useful in understanding alterations in the hepatobiliary disposition of compounds due to drug interactions or disease states. Basolateral transport systems are responsible for translocating molecules across the sinusoidal membrane, whereas active canalicular transport systems are responsible for the biliary excretion of drugs and metabolites. Several transport proteins involved in basolateral transport have been identified including the Na(+)-taurocholate co-transporting polypeptide [NTCP (SLC10A1)], organic anion transporting polypeptides [OATPs (SLCO family)], multidrug resistance-associated proteins [MRPs (ABCC family)], and organic anion and cation transporters [OATs, OCTs (SLC22A family)]. Canalicular transport is mediated predominantly via P-glycoprotein (ABCB1), MRP2 (ABCC2), the bile salt export pump [BSEP (ABCB11)], and the breast cancer resistance protein [BCRP (ABCG2)]. This review summarizes current knowledge regarding these hepatic basolateral and apical transport proteins in terms of substrate specificity, regulation by nuclear hormone receptors and intracellular signaling pathways, genetic differences, and role in drug interactions. Transport knockout models and other systems available for hepatobiliary transport studies also are discussed. This overview of hepatobiliary drug transport summarizes knowledge to date in this rapidly growing field and emphasizes the importance of understanding these fundamental processes in hepatic drug disposition.

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Section: Model Systems For Hepatobiliary Drug Transportmentioning

confidence: 99%

The Complexities of Hepatic Drug Transport: Current Knowledge and Emerging Concepts

Chandra

Brouwer²

2004

Pharm Res

251

169

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“…Use of non-oxygenated buffers for the perfusion appears to be accepted by most authors [3,[9][10][11][12]. One group used oxygenated buffers but the final yield of viable cells was low [13]. There has been no systematic study of the relative merits and demerits of various perfusion conditions to isolate hepatocytes from human liver.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in initial clearance of palmitate by human hepatocytes

Pond¹,

Gordon²,

Bass³

1996

Eur J Clin Investigation

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To determine if the sex differences in clearance of long chain fatty acids by the liver observed in the rat are relevant to humans, the authors isolated hepatocytes from human adult males and females (five per group) and measured the initial (unidirectional) clearance of [3H]-palmitate from buffer containing albumin. The clearance was significantly higher (about twofold) in hepatocytes from females because of a higher permeability of the plasma membrane to the fatty acid. The livers had been perfused with University of Wisconsin (UW) solution and stored for 12-16 h before isolation of the cells. The magnitudes of the clearances in humans were similar to those in the rat when the livers were stored similarly, but lower than in cells isolated from fresh rat liver. When hepatocytes isolated from fresh rat liver were stored in UW solution, clearance of [3H]-palmitate was unaffected. Thus, hepatocytes prepared from intact liver stored for several hours in UW solution do not have as good preservation of function as hepatocytes isolated from fresh liver and then stored in UW solution.

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“…Chemical stability of DEA was determined by incubating 1 and 10 µM DEA in serumfree Williams' Medium E for up to 120 min, and measuring the remaining DEA concentrations. Metabolic activity of the hepatocytes under test article incubation conditions was measured using standard protocols [26,27] with minor modifications. DEA (1 and 10 µM) was incubated with rat, dog, monkey, and human hepatocytes for up to 120 min.…”

Section: Metabolism and Metabolic Profile Of Dea In Rat Dog Monkey And Human Primary Hepatocytesmentioning

confidence: 99%

Azelaic Acid Esters as Pluripotent Immunomodulatory Molecules: Nutritional Supplements or Drugs

Izbicka

Streeper

2021

Nutraceuticals

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Azelaic acid and its esters, the azelates, occur naturally in organisms ranging from plants to humans. We have shown that diethyl azelate (DEA) exhibits a broad range of immunomodulatory activities in vitro and in vivo, and mitigates insulin resistance. To further investigate the therapeutic utility of DEA, we evaluated its mutagenicity in Salmonella typhimurium strains, examined metabolism of DEA in rat, dog, monkey and human primary hepatocytes and in human saliva, determined pharmacokinetics of DEA after an oral dose in rats, and queried its physicochemical properties for drug-like characteristics. DEA was not mutagenic in bacterial strains ± rat liver metabolic activation system S-9. It was chemically unstable in hepatocyte culture medium with a half-life of <1 h and was depleted by the hepatocytes in <5 min, suggesting rapid hepatic metabolism. DEA was also quickly degraded by human saliva in vitro. After an oral administration of DEA to rats, the di- and monoester were undetectable in plasma while the levels of azelaic acid increased over time, reached maximum at <2 h, and declined rapidly thereafter. The observed pharmacological properties of DEA suggest that it has value both as a drug or a nutritional supplement.

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Drug metabolising activity of freshly isolated human hepatocytes.

Cited by 33 publications

References 20 publications

The Complexities of Hepatic Drug Transport: Current Knowledge and Emerging Concepts

The Complexities of Hepatic Drug Transport: Current Knowledge and Emerging Concepts

Sex differences in initial clearance of palmitate by human hepatocytes

Azelaic Acid Esters as Pluripotent Immunomodulatory Molecules: Nutritional Supplements or Drugs

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