Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.

Tjia, John; Back, DJ; Breckenridge, AM

doi:10.1111/j.1365-2125.1989.tb05439.x

Cited by 28 publications

(8 citation statements)

References 14 publications

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“…Previous studies have shown that M17 and M21 are also the main metabolites present in human liver microsomal incubations Tjia et al, 1989), formation being catalysed by cytochrome P450 III A4 (Kronbach et al, 1988).…”

Section: Discussionmentioning

confidence: 95%

Cyclosporin metabolism by the gastrointestinal mucosa.

Tjia

Webber

Back

1991

Brit J Clinical Pharma

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The intestinal mucosal metabolism of the immunosuppressant cyclosporin (CsA) has been studied in vitro using the Ussing chamber technique. Histologically normal colon was obtained from six patients undergoing resections. The mucosal sheets were mounted between two perspex chambers. Three hours after addition of [3H]-CsA (0.2 uCi; 10 FLM) to the mucosal chamber, more than 90% of the radioactivity was present in that chamber. Metabolite analysis, by high performance liquid chromatography, indicated that 77.6 ± 9.2% (mean ± s.d.) of the drug present was CsA, 9.9 ± 4.4% and 8.7 ± 4.7% were the oxidative metabolites M17 and M21 respectively (metabolites identified by co-chromatography with authentic standards). Total metabolite production in tissues from the six individuals was variable (10.1-30.6% at 3 h) and increased over the time period of the study. A different pattern of metabolism was obtained from a single sample of gastric mucosa. More than 20% of CsA was metabolised although neither M17 nor M21 were detected. The results of this study suggest that the gut wall is involved in the first pass metabolism of CsA in vivo and that this could be a contributory factor to the poor systemic availability of CsA seen in some patients.

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Section: Discussionmentioning

confidence: 95%

Cyclosporin metabolism by the gastrointestinal mucosa.

Tjia

Webber

Back

1991

Brit J Clinical Pharma

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“…As expected, administration of propranolol monotherapy as a slow release formulation resulted in delayed absorption with a reduced Cmax, a longer tma x and a greater AUC. It has indeed been demonstrated that calcium antagonists and /?-adrenoceptor blockers are inhibitors of the microsomal enzymes in vitro [14,15]. Therefore, these results indicate that the substrate delivery rate is a determinant of the propranolol-nicardipine interaction.…”

Section: Discussionmentioning

confidence: 71%

Increase in plasma propranolol caused by nicardipine is dependent on the delivery rate of propranolol

Vercruysse

Massart

Dupont

1995

Eur J Clin Pharmacol

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The influence of a single oral dose of nicardipine 30 mg on the pharmacokinetics and pharmacodynamics of propranolol 80 mg given as a conventional release formulation and as a slow release formulation was studied in two separate groups of 12 healthy volunteers. Nicardipine doubled the area under the curve (AUC) and Cmax of propranolol when given as a conventional formulation, but increased it only slightly when given as a slow release formulation. This pharmacokinetic interaction did not result in clinically relevant changes in pharmacodynamic responses. These results indicate that the enhancement of the bioavailability of propranolol by coadministration of nicardipine is dependent on the delivery rate of propranolol, suggesting that the interaction is mainly due to shortterm haemodynamic effects of nicardipine leading to saturation of hepatic enzymes or functional shunting. Methods SubjectsSix healthy male volunteers (23-33 years, mean weight 75 kg) and six healthy female volunteers (24 35 years, mean weight 54 kg)

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“…but not nifedipine, inhibits cyclospori n metabolism (Bourigot et al 1986). This concl usion is supported by the study of Tjia et al (1989), which noted that nicardipine is a potent inhibitor of cyclosporin metabolism in human li ver microsomes.…”

Section: O/her Calcium Channel Blockersmentioning

confidence: 65%

“…Although studies in human liver microsomes show that nifedipine is simi lar to diltiazem and verapam il in inhibition of cyciosporin metabolism (Henricsson & Lindholm 1988;Tjia et al 1989) and that both nifedipine and cyclosporin are substrates for the same cytochrome P450 enzymes (Aoyama el at. 1989;Combalbert et al 1989), no apprcciable change in cyclosporin concentration has been reported in patients treated with both drugs.…”

Section: O/her Calcium Channel Blockersmentioning

confidence: 98%

Pharmacokinetic Drug Interactions with Cyclosporin (Part II)

Yee

McGuire

1990

Clinical Pharmacokinetics

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Part I of this article, which appeared in the previous issue of the Journal, considered the potential mechanisms of drug interactions with cyclosporin, and divided the interacting drugs into 2 categories. Drugs that decrease cyclosporin concentrations (e.g. anti-convulsants, rifampicin, etc.) were dealt with first; the authors then moved on to consider the second category, those that increase cyclosporin concentration (macrolide antibiotics, azole antifungal drugs). Part II continues the survey of this category.

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Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.

Cited by 28 publications

References 14 publications

Cyclosporin metabolism by the gastrointestinal mucosa.

Cyclosporin metabolism by the gastrointestinal mucosa.

Increase in plasma propranolol caused by nicardipine is dependent on the delivery rate of propranolol

Pharmacokinetic Drug Interactions with Cyclosporin (Part II)

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