Use of Sandwich-Cultured Human Hepatocytes to Predict Biliary Clearance of Angiotensin II Receptor Blockers and HMG-CoA Reductase Inhibitors

Abe, Kōji; Bridges, Arlene S.; Brouwer, Kim L. R.

doi:10.1124/dmd.108.023465

Cited by 69 publications

(75 citation statements)

References 23 publications

(35 reference statements)

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“…The accumulation of taurocholate was significantly higher in hepatocytes incubated with standard HBSS than in those incubated with Ca 2ϩ /Mg 2ϩ -free HBSS, and its BEI values ranged from 45 to 70% in SCRH and from 50 to 60% in SCHH in our experiments. These values were comparable to those in previous reports (Liu et al, 1999a;Abe et al, 2009). In contrast, no difference in the accumulation of salicylate in SCRH and SCHH was observed when they were incubated with standard HBSS or Ca 2ϩ /Mg 2ϩ -free HBSS, as demonstrated previously (Liu et al, 1999a).…”

Section: Discussionsupporting

confidence: 82%

“…For example, Fukuda et al (2008) showed that the absolute CL bile, vitro values for some angiotensin II receptor blockers, HMG-CoA reductase inhibitors (statins), and antibiotics were approximately 20-to 200-fold lower than the CL bile, vivo values, although good correlations between CL bile, vitro and CL bile, vivo were observed (Fukuda et al, 2008). Abe et al (2008Abe et al ( , 2009) compared the CL bile, vitro of some angiotensin II receptor blockers and statins with their CL bile, vivo in both sandwich-cultured rat hepatocytes (SCRH) and sandwich-cultured human hepatocytes (SCHH), and these CL bile, vitro values were also 20-to 200-fold lower in the SCRH and approximately 20-fold lower in the SCHH than the CL bile, vivo values (Abe et al, 2008(Abe et al, , 2009). Li et al (2010) tried to improve the in vitro-in vivo correlation of the biliary clearance of drugs using SCRH by introducing an appropriate scaling factor, because CL bile, vitro was approximately 6-fold lower than CL bile, vivo based on a conventional calculation method (Li et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Culture Period-Dependent Changes in the Uptake of Transporter Substrates in Sandwich-Cultured Rat and Human Hepatocytes

Kotani

Maeda²,

Watanabe³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Sandwich-cultured hepatocytes (SCH) are a useful tool for evaluating hepatobiliary drug transport in vitro. Some studies have investigated the in vitro-in vivo correlations of the biliary clearance of drugs using SCH. In most cases, the biliary clearance observed in vivo correlated well with the predicted clearance, but the predicted absolute values were underestimated when based on in vitro experiments with SCH. We hypothesized that the down-regulated function of uptake transporters is one of the causes of this underestimation. Therefore, the uptake of taurocholate, digoxin, pravastatin, and rosuvastatin was investigated in sandwich-cultured rat hepatocytes (SCRH) cultured for 5, 24, 48, and 96 h, and the predicted hepatic clearance from in vitro uptake clearance (CL H, vitro ) was calculated with a dispersion model. In SCRH cultured for 96 h, the saturable uptake of taurocholate, digoxin, pravastatin, and rosuvastatin decreased to 7.5, 3.3, 64, and 23%, respectively, of their uptake in hepatocytes cultured for 5 h, and a better prediction of in vivo hepatic clearance (CL H, vivo ) was achieved when based on CL H, vitro of 5-h-cultured hepatocytes. These results suggest that the uptake activity is considerably reduced in cell culture, even in a sandwich-culture format. In a similar study, we also examined taurocholate and rosuvastatin in sandwich-cultured human hepatocytes (SCHH). Unlike in SCRH, the saturable uptake of these compounds did not differ markedly in SCHH cultured for 5 or 96 h. Thus, the uptake activity in SCHH was maintained relatively well compared with that in SCRH.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Culture Period-Dependent Changes in the Uptake of Transporter Substrates in Sandwich-Cultured Rat and Human Hepatocytes

Kotani

Maeda²,

Watanabe³

et al. 2011

Drug Metab Dispos

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“…However, the prediction of biliary excretion in humans using in vitro tools has not been established. It was reported that in vivo biliary clearance can be predicted from sandwich-cultured hepatocytes in rats and humans (Liu et al, 1999a;Abe et al, 2008Abe et al, , 2009Fukuda et al, 2008;Li et al, 2010). Although apparent biliary clearance using sandwich-cultured rat or human hepatocytes correlates to in vivo values, the differences in biliary clearance between in vitro and in vivo are more than 10-fold.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast with conventional conditions, sandwich-cultured hepatocytes maintain liver-specific functions for several days and exhibit the formation of bile canaliculi and the localization of efflux transporters on the canalicular membrane (LeCluyse et al, 1994;Talamini et al, 1997). Moreover, the biliary clearance of some drugs, such as angiotensin II receptor blockers, HMG-CoA reductase inhibitors, and ␤-lactam antibiotics, showed correlation between sandwich-cultured rat or human hepatocytes and in vivo (Liu et al, 1999a;Abe et al, 2008Abe et al, , 2009Fukuda et al, 2008;Li et al, 2010). Although previous reports have suggested that sandwich-cultured hepatocytes can be used to predict the in vivo biliary clearance of drug candidates, differences in biliary clearance based on the medium or plasma concentration are greater than 10-fold between sandwich-cultured rat or human hepatocytes and in vivo values.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Biliary Clearance Should Be Predicted by Intrinsic Biliary Clearance in Sandwich-Cultured Hepatocytes

Nakakariya

Ono²,

Amano³

et al. 2011

Drug Metab Dispos

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ABSTRACT:It has been reported that in vivo biliary clearance can be predicted using sandwich-cultured rat and human hepatocytes. The predicted apparent biliary clearance (CL bile, app ) from sandwichcultured rat hepatocytes (SCRH) based on medium concentrations correlates to in vivo CL bile, app based on plasma concentrations of angiotensin II receptor blockers (ARBs), HMG-CoA reductase inhibitors (statins), ␤-lactam antibiotics, and topotecan. However, the predicted biliary clearance from SCRH was 7-to 300-fold lower than in vivo biliary clearance. We speculated that the process of biliary excretion might not have been evaluated using sandwichcultured hepatocytes. To evaluate this issue, intrinsic biliary clearance (CL bile, int ) based on intracellular compound concentrations was evaluated to investigate the in vitro-in vivo correlation of this process among ARBs, statins, ␤-lactam antibiotics, and topotecan. Intrinsic biliary clearance in SCRH correlated to in vivo values obtained by constant intravenous infusion of six compounds, but not rosuvastatin and cefmetazole, to rats. Moreover, differences between SCRH and in vivo CL bile, int (0.7-6-fold) were much smaller than those of CL bile, app (7-300-fold). Therefore, in vivo CL bile, int is more accurately reflected using SCRH than CL bile, app . In conclusion, to predict in vivo biliary clearance more accurately, CL bile, int should be evaluated instead of CL bile, app between SCRH and in vivo.

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“…In vitro predictions can be carried out in sandwichcultured rat or human hepatocytes, which preserve cell polarity and bile canaliculi (15,16), but uptake transporter expression is not well preserved in sandwich-cultured rat hepatocytes (17) and biliary clearance can be rate limited by uptake (18). Several studies have demonstrated that in vitro measures correlate with, but underpredict, in vivo biliary clearance (19)(20)(21). Bile duct cannulation in rats is often performed, but may not scale to humans, especially as rats have greater rates of bile flow (22) and canalicular efflux transport (23), as well as increased expression (24,25) of canalicular efflux transporters.…”

Section: Introductionmentioning

confidence: 99%

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Hosey-Cojocari

Broccatelli

Benet

2014

AAPS J

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Abstract. Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

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Use of Sandwich-Cultured Human Hepatocytes to Predict Biliary Clearance of Angiotensin II Receptor Blockers and HMG-CoA Reductase Inhibitors

Cited by 69 publications

References 23 publications

Culture Period-Dependent Changes in the Uptake of Transporter Substrates in Sandwich-Cultured Rat and Human Hepatocytes

Culture Period-Dependent Changes in the Uptake of Transporter Substrates in Sandwich-Cultured Rat and Human Hepatocytes

In Vivo Biliary Clearance Should Be Predicted by Intrinsic Biliary Clearance in Sandwich-Cultured Hepatocytes

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

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