Effect of Oral Ketoconazole on First‐pass Effect of Nifedipine After Oral Administration in Dogs

Kuroha, Masanori; Kayaba, Hideki; Kishimoto, Shizuka; Khalil, Waleed F.; Shimoda, Minoru; Kokue, Eiichi

doi:10.1002/jps.10086

Cited by 26 publications

(22 citation statements)

References 17 publications

(19 reference statements)

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“…The concomitant administration of oral KTZ and i.v. 0.5 mg/kg nifedipine to dogs showed 1.83-fold increase in AUC, and 1.73-and 1.2-fold decreases in the CL and V dss , respectively (Kuroha et al, 2002). Similarly, coadministration of 12.5 mg of almotriptan, a selective 5-HT 1B/1D agonist, and 400 mg of KTZ to healthy volunteers generated a 44% decrease in the V z /F of almotriptan (Fleishaker et al, 2003).…”

Section: Discussionmentioning

confidence: 89%

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Shayeganpour¹,

El‐Kadi²,

Brocks³

2005

Drug Metab Dispos

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ABSTRACT:In humans, cytochrome P450 3A (CYP3A4) is a major enzyme involved in the metabolism of amiodarone (AM) to its major metabolite, desethylamiodarone (DEA). In rat, a commonly used animal model, metabolism of AM has not been well studied. To determine whether DEA is formed by CYP3A isoenzymes in the rat, microsomal protein was harvested from liver and intestine of male Sprague-Dawley rats. The metabolism of AM in each tissue was assessed utilizing chemical and immunological inhibitors. Ketoconazole, a presumed inhibitor of CYP3A1/2, significantly inhibited formation of DEA by hepatic and intestinal microsomes. However, based on the DEA formation kinetics in both microsomal preparations, it appeared that more than one cytochrome P450 enzyme was involved in the process. Coincubation of AM with microsomes and anti-CYP3A2 confirmed the role of CYP3A2 in the metabolism of AM in liver. DEA was also formed by rat recombinant CYP1A1 and CYP3A1, and was inhibited by ketoconazole; hence the participation of these enzymes in the intestinal DEA formation is likely. However, anti-CYP2B1/2 or -CYP1A2 antibodies had no effect on DEA formation. In rats given oral or intravenous AM, oral ketoconazole caused significant increases in area under the concentration versus time curve (AUC) of oral and i.v. treated rats and greater than 50% decreases in the total body clearance and V dss of i.v. treated rats. Although low to undetectable concentrations of DEA were a limitation for determination of AUC of DEA in vivo, it was confirmed that ketoconazole could cause a significant increase in AM concentrations in rat.Amiodarone (AM) is an iodinated class III antiarrhythmic benzofuran derivative with extensive clinical usage (Trivier et al., 1993;Soyama et al., 2002) in the treatment of life-threatening ventricular and supraventricular arrhythmias (Naccarelli et al., 2000). AM undergoes extensive hepatic biotransformation (Trivier et al., 1993;Soyama et al., 2002). Among the five pathways involved in the metabolism of AM (N-deethylation, hydroxylation, O-dealkylation, deiodination, and glucuronidation), N-dealkylation is most important in humans (Trivier et al., 1993;Soyama et al., 2002). The dealkylated metabolite, desethylamiodarone (DEA) shares some of the pharmacological and toxicological properties of AM. For instance, some of the electrocardiographic changes observed after long-term therapy with AM might be related to DEA (Kharidia and Eddington, 1996;Kodama et al., 1999). In addition, both AM and DEA inhibit the intracellular conversion of thyroxine to triiodothyronine. This inhibition may be related to some cardiotoxic effects of AM such as bradycardia and reduced myocardial oxygen consumption, and may explain the hypothyroid-like condition observed after chronic administration of AM (Hudig et al., 1994;Kodama et al., 1999).AM possesses a very large pharmacokinetic volume of distribution (V d ) and extensive tissue distribution, and, in turn, a long terminal half-life (t 1/2 ) in rat and human plasma (Pollak et al., 2000;Shaye...

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Section: Discussionmentioning

confidence: 89%

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Shayeganpour¹,

El‐Kadi²,

Brocks³

2005

Drug Metab Dispos

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“…Co-administration of ketoconazole and rifampicin dramatically affects the pharmacokinetic characteristics of the drugs with high hepatic extraction ratio and intensive CYP3A-mediated first-pass metabolism, such as nifedipine and buspirone [21][22][23] . In the current study, significant drugdrug interactions between GLS4 and ketoconazole or rifampicin were observed in dogs.…”

Section: Pharmacokinetics Of Gls4 Affected By Rifampicinmentioning

confidence: 99%

Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs

Zhou

Gao

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs. Methods: Dog and human liver microsomes and CYP3A4 were incubated with [14 C]GLS4 for 15 min and then analyzed using a HPLCdynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry. Results: The metabolic profile of [14 C]GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively. Conclusion: GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice.

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“…Moreover, other researchers also reported drug interaction of KTZ with Table 1. cyclosporine in human [19] and dog [5,14] and with midazolam in human [3,7] and dog [10]. The extent of inhibitory effects of KTZ on MDZ1'H and MDZ4H seems to be quite different among animal species.…”

Section: Discussionmentioning

confidence: 99%

“…They also reported that CIM, itraconazole and ERY decreased hepatic intrinsic clearance of MDZ by 30%, 60%, and 80%, and hepatic clearance by 20%, 50%, and 70%, respectively. In dogs concomitant use of ketoconazole (KTZ) decreased the total body clearance (Cltot) of nifedipine by 71% [10], that of MDZ by 71% [11], and that of quinidine (QUN) by about 60% [13].Although it is well known that cats have quite low or negligible activities of UDP-glucuronosyltransferase, information about CYP3A-mediated drug metabolism is limited in cats. However, Shah et al [22] have recently reported that 1'-and 4-hydroxylation of MDZ is mainly catalysed by CYP3A also in cats.…”

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confidence: 99%

Inhibitory Effects of Ketoconazole, Cimetidine and Erythromycin on Hepatic CYP3A Activities in Cats

Shah

Sasaki

Hayashi

et al. 2009

The Journal of Veterinary Medical Science

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Inhibitory effects of ketoconazole (KTZ), cimetidine (CIM), and erythromycin (ERY) were examined on CYP3A activities. Midazolam 1'-and 4-hydroxylation (MDZ1'H and MDZ4H) were used to determine CYP3A activities in hepatic microsomes obtained from cats (n=4). The results showed that, all the examined drugs inhibited the reactions in a noncompetitive manner. The inhibitory constants (Ki) of KTZ were 2.80  0.70 and 115  28 M for MDZ1'H and MDZ4H, respectively. Those of CIM were 3.13 and 3.27 mM and of ERY were 3.14 and 6.41 mM for MDZ1'H and MDZ4H, respectively. Mechanism-based inhibition was also examined in this study. KTZ significantly reduced MDZ reactions in a time-dependent manner; while CIM and ERY did not. Also, the effects of KTZ and CIM on the pharmacokinetics of quinidine (QUN) were studied. KTZ or CIM (10 mg/kg/day, for one week) was given orally to cats (n=5). QUN (2 mg/kg, i. v.) was injected 2 hr after the last dose of KTZ or CIM. The analysis of the obtained pharmacokinetic parameters showed that, KTZ significantly reduced total body clearance of QUN by 35%, while CIM did not. These results suggest that, KTZ inhibits CYP3A activities (both in vitro and in vivo), but CIM does not. In clinical practice, therefore, KTZ may result in inhibition based drug-drug interaction with CYP3A substrates in cat patients, whereas CIM and ERY are unlikely to lead to interaction involving CYP3A substrates. The cytochrome P450 (CYP)-mediated drug metabolism is one of most important elimination pass ways in drug elimination. Of the CYP enzymes, CYP3A is the most important subfamily in human, because it catalyses biotransformation of approximately half of currently available drugs in clinical practice [1, 8]. The reduction in CYP3A activities, therefore , may result in serious adverse effects in drug therapy, because of increased bioavailability and decreased clearance of drugs. Consequently, many researchers extensively studied the possible inhibitory effects of drugs on CYP3A activities [11, 25, 27]. As a result, many drugs were classified as a CYP3A inhibitor, including azole antifungal agents [17, 26, 32], cimetidine (CIM) [4, 9, 15], and macrolide antibiotics [32] in humans or dogs. Many investigators have also demonstrated drug-drug interaction between CYP3A inhibitors and CYP3A substrates. In human, Yamano et al. [30] reported increasing plasma concentrations of midazolam (MDZ) with concomitant administration of CIM, itracona-zole or erythromycin (ERY). They also reported that CIM, itraconazole and ERY decreased hepatic intrinsic clearance of MDZ by 30%, 60%, and 80%, and hepatic clearance by 20%, 50%, and 70%, respectively. In dogs concomitant use of ketoconazole (KTZ) decreased the total body clearance (Cltot) of nifedipine by 71% [10], that of MDZ by 71% [11], and that of quinidine (QUN) by about 60% [13]. Although it is well known that cats have quite low or negligible activities of UDP-glucuronosyltransferase, information about CYP3A-mediated drug metabolism is limited in cats. However, Shah et al. [22] ha...

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Effect of Oral Ketoconazole on First‐pass Effect of Nifedipine After Oral Administration in Dogs

Cited by 26 publications

References 17 publications

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs

Inhibitory Effects of Ketoconazole, Cimetidine and Erythromycin on Hepatic CYP3A Activities in Cats

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