Effect of Oral Ketoconazole on Intestinal First-Pass Effect of Midazolam and Fexofenadine in Cynomolgus Monkeys

Ogasawara, Akihito; Kume, Toshiyuki; Kazama, Emiko

doi:10.1124/dmd.106.011288

Cited by 52 publications

(48 citation statements)

References 55 publications

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“…Since many P-gp related drug-drug interactions have been reported, 15,16) P-gp is considered to be the most important ABC transporter with regard to drug efficacy. Therefore, it is thought that information on the changes in P-gp expression and localization induced by diseases would be useful for clinicians performing drug therapy.…”

Section: Discussionmentioning

confidence: 99%

Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

Takizawa

Kishimoto

Kitazato

et al. 2011

Biological & Pharmaceutical Bulletin

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ATP binding cassette (ABC) transporters form one of the largest families of membrane transport proteins and are expressed in all organisms. They have been studied extensively and play a vital role in many cellular processes. ABC transporters are responsible for the multidrug resistance of cancer cells 1) but may also be capable of transporting several substrates such as metal ions, peptides, amino acids, sugars, and a large number of hydrophobic compounds and metabolites across the plasma membrane as well as intracellular membranes.2) ABC transporters play important roles in the defense mechanisms of several tissues through the excretion of toxic compounds and their metabolites. 3,4) In addition, the expression levels of the transporters are tightly regulated during tissue defense. 5)P-Glycoprotein (P-gp) is a typical ABC transporter. P-gp, which plays a very important role in drug therapy, was first discovered in 1976 as an efflux pump in a colchicine-resistant cell line, and 10 years later, the gene for P-gp was encoded. It is the most extensively studied of all of the ABC transporters.During small intestine grafting, rejection and ischemia/ reperfusion (I/R) injury are important problems. Immunosuppressive therapy is always required after transplantation. Since transplantation depends on a delicate balance between immunosuppression and rejection, the maintenance of adequate blood concentrations of immunosuppressants is critical. Cyclosporine A and tacrolimus are representative P-gp substrates. Therefore, P-gp controls the efficacies of these immunosuppressants. Information about the changes in P-gp induced by intestinal I/R would be useful for clinicians performing immunosuppressive therapy. We previously reported in in vitro 6) and in vivo 7-9) studies that I/R influences the function and expression of P-gp. In these reports, a correlation was found between the function of P-gp 1 h after reperfusion and the expression level of P-gp, but no such relationship was recognized 24 h after reperfusion. 7,8) It was suggested that this was due to functional abnormalities or abnormal localization of P-gp.In the present study, we examined whether abnormal P-gp localization is induced by intestinal I/R. Moreover, the mechanism and factors responsible for this phenomenon were also examined. MATERIALS AND METHODS MaterialsAll reagents were of analytical grade or better. Animals and Experimental Design Male Wistar/ST rats (8 weeks old) were purchased from Japan SLC Ltd. (Shizuoka, Japan). All animal experiments were performed according to the guidelines of Tokyo University of Pharmacy and Life Sciences. The animals were fasted for 18 h before the start of the experiment. Water was given freely during fasting. We have previously reported an in vivo intestinal I/R model that was produced using a spring scale and surgical sutures.7-9) Briefly, the superior mesenteric artery and vein in rats were occluded by lifting them using surgical-sutures (Natsume No. 3) connected to a spring balance for 1 h (ischemia condition), before r...

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Section: Discussionmentioning

confidence: 99%

Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

Takizawa

Kishimoto

Kitazato

et al. 2011

Biological & Pharmaceutical Bulletin

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“…The hepatic metabolism of specific human CYP2C substrates, such as tolbutamide, warfarin, and (S)-mephenytoin, is known to be impaired more in dogs than in humans [13], whereas metabolism studies using liver microsomes demonstrated that the metabolism of human CYP2D substrates, such as bufuralol and dextromethorphan, was similar in humans and dogs [10,11,14]. Monkeys were originally considered to have pharmacokinetic properties similar to those of humans due to genetic similarities, however, previous studies showed that the bioavailability (BA) of some drugs including human CYP3A substrates was markedly lower in monkeys than in humans [7,[15][16][17][18][19][20]. Monkeys have also been shown to exhibit higher CYP activities for human CYP2D6 substrates in their liver microsomes than humans [10,12,16,21,22].…”

Section: Introductionmentioning

confidence: 99%

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

S¹

2015

J Drug Metab Toxicol

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To clarify species differences in the pharmacokinetic parameters of cytochrome P450 (CYP) activities between humans and experimental animals, we assessed several CYP activities in mice, rats, dogs, monkeys, and microminipigs, using the simultaneous administration of typical human CYP substrates, such as caffeine (human CYP1A2 substrate), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A), to these animals. The intrinsic clearance (CL int ) of these 5 substrates was also examined using the liver microsomes of humans and the experimental animals. The high bioavailabilities (BAs) and low CL int values of caffeine in the experimental animals were similar to those in humans. Mice and monkeys had lower BAs and higher CL int values of losartan than those in humans. Mice, rats, and monkeys had lower BAs and higher CL int values of omeprazole than those in humans. The lowest BAs of dextromethorphan were observed in monkeys and microminipigs, and only the CL int in dogs was similar to that in humans. The BA of midazolam in microminipigs only was similar to that in humans, while the CL int values in the other animals were similar to that in humans. These results indicated that in vitro and in vivo experimental data obtained using multiple animals including microminipigs are useful for predicting human pharmacokinetics.

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“…Several studies have demonstrated that monkeys are particularly useful in interspecies scaling for predicting human pharmacokinetics (Ward and Smith, 2004;Ward et al, 2005;Sakuda et al, 2006;Ogasawara et al, 2007). Recent studies have identified a number of P450 cDNAs from cynomolgus monkeys, including those of CYP3A8 and CYP3A5, which show high sequence identities (94 -95%) with the orthologous human CYP3A4 and CYP3A5, respectively (Uno et al, 2007(Uno et al, , 2010Iwasaki and Uno, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have identified a number of P450 cDNAs from cynomolgus monkeys, including those of CYP3A8 and CYP3A5, which show high sequence identities (94 -95%) with the orthologous human CYP3A4 and CYP3A5, respectively (Uno et al, 2007(Uno et al, , 2010Iwasaki and Uno, 2009). Furthermore, when an oral dose of CYP3A substrates, such as midazolam (MDZ) and simvastatin, was coadministered with typical CYP3A inhibitors, these monkeys showed markedly higher plasma concentrations than those who received a dose of substrate alone (Kanazu et al, 2004;Ogasawara et al, 2007Ogasawara et al, , 2009a. These findings suggest that monkeys can be used to investigate the underlying mechanism of and to predict the likelihood of clinical DDIs when CYP3A inhibition is involved.…”

Section: Introductionmentioning

confidence: 99%

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

Ohtsuka¹,

Yoshikawa²,

Kozakai³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Induction of the cytochrome P450 (P450) enzyme is a major concern in the drug discovery processes. To predict the clinical significance of enzyme induction, it is helpful to investigate pharmacokinetic alterations of a coadministered drug in a suitable animal model. In this study, we focus on the induction of CYP3A, which is involved in the metabolism of approximately 50% of marketed drugs and is inducible in both the liver and intestine. As a marker substrate for CYP3A activity, alprazolam (APZ) was selected and characterized using recombinant CYP3A enzymes expressed in Escherichia coli. Both human CYP3A4 and its cynomolgus P450 ortholog predominantly catalyzed APZ 4-hydroxylation with sigmoidal kinetics. When administered intravenously and orally to cynomolgus monkeys, APZ had moderate clearance; its first-pass extraction ratio after oral dosing was estimated to be 0.09 in the liver and 0.45 in the intestine. Pretreatment with multiple doses of rifampicin (20 mg/kg p.o. for 5 days), a known CYP3A inducer, significantly decreased plasma concentrations of APZ after intravenous and oral administrations (0.5 mg/kg), and first-pass extraction ratios were increased to 0.39 in the liver and 0.63 in the intestine. The results were comparable to those obtained in clinical drug-drug interaction (DDI) reports related to CYP3A induction, although the rate of recovery of CYP3A activity seemed to be slower than rates estimated in clinical studies. In conclusion, pharmacokinetic studies using APZ as a probe in monkeys may provide useful information regarding the prediction of clinical DDIs due to CYP3A induction.

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Effect of Oral Ketoconazole on Intestinal First-Pass Effect of Midazolam and Fexofenadine in Cynomolgus Monkeys

Cited by 52 publications

References 55 publications

Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

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

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