Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Ohtsuka, Tatsuyuki; Yoshikawa, Takahiro; Kozakai, Kazumasa; Tsuneto, Yumi; Uno, Yasuhiro; Utoh, Masahiro; Yamazaki, Hiroshi; Kume, Toshiyuki

doi:10.1124/dmd.110.032656

Cited by 27 publications

(20 citation statements)

References 41 publications

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“…The magnitude of hepatic DDI, estimated as the value of (F H 9/F H )·(CL total / CL total 9), was higher than that in a clinical DDI report, in which C max and AUC po of pitavastatin increased by 2.0-and 1.3-fold, respectively (CDERb, 2009). The reason for the apparent discrepancy was not 3.2 6 0.9 3.6 6 1.6 F H 9/F H 1.4 6 0.1 1.4 6 0.1 (F H 9/F H )·(CL total /CL total 9) 4.5 6 1.1 5.0 6 2.0 dmd.aspetjournals.org attributable to the dose of or the plasma exposure to RIF; the geometric mean of C max in the clinical study was 8.9 mg/ml after oral dosing at 600 mg and that in monkeys was 10.2 mg/ml after an oral dose of 25 mg/kg, as we reported previously (Ohtsuka et al, 2010). Rather, the dosing regimen was substantially different in the clinical study, in which pitavastatin was administered after multiple doses of RIF; therefore, the inhibitory effect on the hepatic uptake of pitavastatin may be masked by the induction of metabolizing enzymes and/or transporters.…”

Section: Discussionsupporting

confidence: 59%

“…Hence, monkeys may be useful as a preclinical in vivo DDI model involving OATP inhibition. Previously, we reported that clinical DDIs related to P-glycoprotein (P-gp)-mediated transport and cytochrome P450 3A (CYP3A)-mediated metabolism were reproduced in cynomolgus monkeys (Ogasawara et al, 2007(Ogasawara et al, , 2009aOhtsuka et al, 2010). Tahara et al (2006) reported that monkeys (rather than rats) were useful for predicting the DDI risks involving renal tubular transport in humans.…”

Section: Introductionmentioning

confidence: 99%

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Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

et al. 2013

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Drug-drug interactions (DDIs) caused by the inhibition of hepatic uptake transporters such as organic anion transporting polypeptide (OATP) can affect therapeutic efficacy and cause adverse reactions. We investigated the potential utility of pitavastatin as an in vivo probe substrate for preclinically studying OATP-mediated DDIs using cynomolgus monkeys. Cyclosporine A (CsA) and rifampicin (RIF), typical OATP inhibitors, inhibited active uptake of pitavastatin into monkey hepatocytes with half-maximal inhibitory concentration values comparable with those in human hepatocytes. CsA and RIF increased the area under the plasma concentration-time curve (AUC) of intravenously administered pitavastatin in cynomolgus monkeys by 3.2-and 3.6-fold, respectively. In addition, there was no apparent prolongation of the elimination half-life of pitavastatin due to the decrease in both hepatic clearance and volume of distribution. These findings suggest that DDIs were caused by the inhibition of hepatic uptake of pitavastatin. CsA and RIF increased the AUC of orally administered pitavastatin by 10.6-and 14.8-fold, respectively, which was additionally caused by the effect of the CsA and RIF in the gastrointestinal tract. Hepatic contribution to the overall DDI for oral pitavastatin with CsA was calculated from the changes in hepatic availability and clearance, and it was shown that the magnitude of hepatic DDI was comparable between the present study and the clinical study. In conclusion, pharmacokinetic studies using pitavastatin as a probe in combination with drug candidates in cynomolgus monkeys are useful to support the assessment of potential clinical DDIs involving hepatic uptake transporters.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

et al. 2013

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“…In the stage of drug discovery and development, in vivo drug interrelation studies with human probe drugs have been carried out using whole body of monkeys. 24) Special attention should be required when enzymatic and pharmacokinetic data such as drug interactions are extrapolated from monkeys to humans.…”

Section: N-demethylationmentioning

confidence: 99%

Species Difference between Cynomolgus Monkeys and Humans on Cytochromes P450 2D and 3A-Dependent Drug Oxidation Activities in Liver Microsomes

Emoto

Iwasaki

Koizumi

et al. 2011

JOURNAL OF HEALTH SCIENCE

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Cynomolgus monkeys [Macaca fascicularis (mf)] are widely used to determine pharmacokinetics and toxicological potential of many drug candidates as human models in the drug discovery and development. Cytochrome P450s (P450, CYP), one of the most important enzymes in drug metabolism, in monkey livers are generally similar to corresponding human P450s exhibiting high degrees of homologies in cDNAs and amino acid sequences. Species differences regarding important liver P450 3A and 2D function were examined between cynomolgus monkeys and humans using typical human P450 probe reactions using midazolam (a P450 3A marker), dextromethorphan and bufuralol (P450 2D markers). P450 3A-mediated midazolam 1 -hydroxylation activities in liver microsomes from individual monkey were highly correlated with midazolam 4 -hydroxylation activities but not correlated with dextromethorphan N-demethylation activities. Recombinant monkey CYP2D17 and CYP2D44 catalyzed dextromethorphan O-and N-demethylations as well as monkey mfCYP3A4 and mfCYP3A5 did. On the other hand, contributions of corresponding P450 2D6 and P450 3A4/5 to dextromethorphan N-and O-demethylations, in human liver microsomes were negligible under the present conditions. From these results, monkey P450 2D and 3A enzymes might have broader substrate specificity toward dextromethorphan oxidation than those in human livers. Special attention should be paid when enzymatic and pharmacokinetic data are extrapolated from monkeys to humans.

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“…The induction potency of cmCYP3A4 (3A8) by RIF, which is known as a cmCYP3A4 (3A8) inducer, 13,14) was examined with the cells differentiated from cmESCs. The expression of cmCYP3A4 (3A8) mRNA was significantly induced by RIF in the cmESC-derived hepatocytes (Fig.…”

Section: Effects Of Rif On the Expression Level And Activity Of Cmcypmentioning

confidence: 99%

Differentiation of Monkey Embryonic Stem Cells to Hepatocytes by Feeder-Free Dispersion Culture and Expression Analyses of Cytochrome P450 Enzymes Responsible for Drug Metabolism

Maruyama

Matsunaga

Yamaori

et al. 2013

Biological & Pharmaceutical Bulletin

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We reported previously that monkey embryonic stem cells (ESCs) were differentiated into hepatocytes by formation of embryoid bodies (EBs). However, this EB formation method is not always efficient for assays using a large number of samples simultaneously. A dispersion culture system, one of the differentiation methods without EB formation, is able to more efficiently provide a large number of feeder-free undifferentiated cells. A previous study demonstrated the effectiveness of the Rho-associated kinase inhibitor Y-27632 for feeder-free dispersion culture and induction of differentiation of monkey ESCs into neural cells. In the present study, the induction of differentiation of cynomolgus monkey ESCs (cmESCs) into hepatocytes was performed by the dispersion culture method, and the expression and drug inducibility of cytochrome P450 (CYP) enzymes in these hepatocytes were examined. The cmESCs were successfully differentiated into hepatocytes under feeder-free dispersion culture conditions supplemented with Y-27632. The hepatocytes differentiated from cmESCs expressed the mRNAs for three hepatocyte marker genes (α-fetoprotein, albumin, CYP7A1) and several CYP enzymes, as measured by real-time polymerase chain reaction. In particular, the basal expression of cmCYP3A4 (3A8) in these hepatocytes was detected at mRNA and enzyme activity (testosterone 6β-hydroxylation) levels. Furthermore, the expression and activity of cmCYP3A4 (3A8) were significantly upregulated by rifampicin. These results indicated the effectiveness of Y-27632 supplementation for feeder-free dispersed culture and induction of differentiation into hepatocytes, and the expression of functional CYP enzyme(s) in cmESC-derived hepatic cells.Key words embryonic stem cell; differentiation; hepatocyte; monkey; cytochrome P450; feeder-free dispersed culture Investigation of drug metabolism with human hepatocytes is important in the early stages of drug development. However, primary human hepatocytes are short-lived and cannot be maintained in culture over the long term. In addition, there are large donor-dependent variations in drug metabolism. On the other hand, human embryonic stem cells (ESCs) are able to replicate infinitely and differentiate into various types of somatic cells including germ cells.1) Thus, they represent an attractive source to provide large numbers of cells that can be utilized for the development of candidate drug-screening strategies in place of primary cells.2) However, ethical and legal restrictions have limited the availability of human ESCs. The phenotype of human ESCs is known to closely resemble that of monkey ESCs but not mouse ESCs with regard to morphology, leukemia inhibitory factor responsiveness, gene expression profiles, and some disease models.1,3-6) Thus, monkey ESCs are a more suitable model for preclinical research of drug development. In particular, hepatocytes derived from monkey ESCs may be useful for pharmacokinetic studies, such as investigation of drug-drug interactions and the inducibility of drug-metabolizi...

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Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Cited by 27 publications

References 41 publications

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

Species Difference between Cynomolgus Monkeys and Humans on Cytochromes P450 2D and 3A-Dependent Drug Oxidation Activities in Liver Microsomes

Differentiation of Monkey Embryonic Stem Cells to Hepatocytes by Feeder-Free Dispersion Culture and Expression Analyses of Cytochrome P450 Enzymes Responsible for Drug Metabolism

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