Effect of cimetidine on pharmacokinetics of orally administered cyclosporine in healthy dogs

Daigle, Jenise Coyne; Hosgood, Giselle; Foil, C. S.; Hunter, R. P.

doi:10.2460/ajvr.2001.62.1046

Cited by 25 publications

(31 citation statements)

References 21 publications

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“…Whole blood peak and trough concentrations of CSA when administered at 5.0 mg ⁄ kg in this study were within the range of those documented in previous studies. 10,28 Although 2 h blood CSA concentrations in humans are predictive of acute rejection and clinical outcome in solid organ transplantation, a study of 97 dogs with AD treated with CSA at a mean dose of 4.6 mg ⁄ kg orally once daily for 28 days found no significant correlation between clinical improvement and whole blood CSA concentrations. 27,28,31,32 As skin is likely to be the target organ for treatment of atopic dermatitis, the concentration of CSA achieved in the skin may be important in determining the clinical response to CSA therapy.…”

Section: Discussionmentioning

confidence: 99%

“…21,35 The degree of interindividual variability in whole blood CSA concentrations was comparable to those reported in previous studies. 10,28 Interindividual variation in whole blood CSA concentrations is a well-recognized phenomenon in humans and is associated with a variety of factors, such as age, race and comorbidities. 36 The genetic expression of a functional polymorphism of the CYP 450 enzyme responsible for CSA metabolism as well as ABCB1 genotypes have been the focus of recent research on the interindividual variation of CSA concentration in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that neither metoclopramide nor cimetidine, both P450 inhibitors, have any effect on the pharmacokinetic profile of concurrently administered CSA. 10,11 Grapefruit juice and powdered whole grapefruit may variably affect the pharmacokinetic parameters of CSA in dogs. 11,12 Ketoconazole (KTZ) is a potent inhibitor of numerous cytochrome P450 enzymes, including CYP 2B11 and 3A12 ⁄ 26.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Ketoconazole on Whole Blood and Skin Ciclosporin Concentrations in Dogs

Gray¹,

Hillier²,

Cole³

et al. 2013

Advances in Veterinary Dermatology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Effect of Ketoconazole on Whole Blood and Skin Ciclosporin Concentrations in Dogs

Gray¹,

Hillier²,

Cole³

et al. 2013

Advances in Veterinary Dermatology

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“…A similar effect has been demonstrated in the dog with clarithromycin and erythromycin, whereas clindamycin and lincomycin did not increase ciclosporin availability (Steffan 2004, Katayama and others 2013). The interaction between ciclosporin and cimetidine, an H2 receptor antagonist and a potent inhibitor of the CYP 3A system, has been studied in dogs (Daigle and others 2001). This work demonstrated that cimetidine delayed but did not decrease the rate of absorption of ciclosporin.…”

Section: Clinical Aspects Of Drug Interactionsmentioning

confidence: 99%

Ciclosporin 10 years on: indications and efficacy

Forsythe¹,

Paterson

2014

Veterinary Record

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Ciclosporin is a lipophilic cyclic polypeptide with powerful immunosuppressive and immunomodulatory properties that has been used in veterinary medicine for two decades. It is a calcineurin inhibitor whose principal mode of action is to inhibit T cell activation. The drug is principally absorbed from the small intestine and is metabolised in the intestine and liver by the cytochrome P450 enzyme system. Ciclosporin is known to interact with a wide range of pharmacological agents. Numerous studies have demonstrated good efficacy for the management of canine atopic dermatitis and this has been a licensed indication since 2003. In addition to the treatment of atopic dermatitis, it has been used as an aid in the management of numerous other dermatological conditions in animals including perianal fistulation, sebaceous adenitis, pododermatitis, chronic otitis externa and pemphigus foliaceus. This article reviews the mode of action, pharmacokinetics, indications for use and efficacy of ciclosporin in veterinary dermatology.

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“…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.…”

mentioning

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 cimetidine on pharmacokinetics of orally administered cyclosporine in healthy dogs

Cited by 25 publications

References 21 publications

The Effect of Ketoconazole on Whole Blood and Skin Ciclosporin Concentrations in Dogs

The Effect of Ketoconazole on Whole Blood and Skin Ciclosporin Concentrations in Dogs

Ciclosporin 10 years on: indications and efficacy

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

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