Cyclosporin plasma concentrations

Two molecular mechanisms for the interactions have been established. First, both hypericin and hy-perforin, two of the pharmacologically active constituents of the herb, cause induction of the enzyme CYP3A4 which is responsible for much of the metabolism of many commonly used drugs. Giving SJW to patients also taking the immunosuppressant, cyclosporine, which is metabolized primarily by CYP3A4, has led to near-rejection of transplanted organs as cyclosporine plasma concentrations fell due to increased metabolism. The same mechanism has led to reduced efficacy of indinavir in patients... 

The co-administration of drugs which induce the metabolic enzymes in the liver or small intestine can reduce the plasma concentrations of drugs which are substrates of the enzyme, leading to reduced drug effects. For example, the plasma concentrations of many drugs which are substrates of the enzyme CYP3A4, such as cyclosporine, are decreased by coadministration of rifampicin, which is an inducer of CYP3A4. 

St. John s wort, which has become very popular for the treatment of depression, has been shown to induce intestinal P-gp and intestinal and hepatic CYP3A4 in humans [140]. That mechanism explains the significant reduction in cyclosporin and anti-aids (e.g., indinavir) plasma concentrations. It is likely that similar effects will be noted with the compounds listed in Table 8 (although the effects noted in Table 8 are in the opposite direction of those seen in the presence of St. John s wort). 

There are occasional anomalies to the rule that food reduces and delays peak plasma concentration. The anti-fungal drug, griseofulvin, has enhanced absorption if taken with a meal - possibly because it becomes emulsified by bile salts and passes more readily into the lymphatic drainage of the gut which bypasses the liver, entering the venous system directly. The immuno-suppressant cyclosporin, and calcium salts in general, show a similar increase in absorption when taken with a fatty meal. 

Finally, developmental differences in pharmacodynamics can be observed in the absence of age-associated changes in the dose versus plasma concentration relationship. Marshall and Kearns demonstrated developmental differences in the pharmacodynamics of cyclosporin. In this study, the IC50 for interleukin-2 (IL-2) expression observed in peripheral blood monocytes obtained from infants less than 12 months of age and exposed in vitro to cyclosporin was approximately 50% of the value observed for older children. In this particular example, the pharmacodynamic differences appeared not to be the consequence of developmental dependence on pharmacokinetics but rather, in the true drug-receptor interaction. 

Cyclosporin A is slowly but extensively metabolized. The biotransformation pathway and the pattern of the generated metabolites are similar in humans and animals. Approximately 17 single metabolites have been detected so far, all of which are present in considerably lower plasma concentration than cyclosporin A itself [46]. Eleven ether-extractable compounds have been isolated from urine of dog and man and from rat bile and faeces using preparative HPLC and thin-layer chromatography [43]. Structural assignments for these... 

Sgoutas et al. [151] determined the cyclosporine distribution in plasma from fasted and nonfasted patients, and these data are shown in Table 8. An increased proportion of cyclosporine was associated with the TRL in the nonfasted state compared with fasted patients with a corresponding decrease in LDL and HDL CY levels. An extreme example of altered cyclosporine plasma distribution has also been reported in a case study of a patient with severe hypertriglyceridemia [152], This was characterized by huge increases in plasma chylomicron concentrations (with plasma TG concentrations concentrations up to 264 mg/ mL-1) and much higher than expected plasma concentrations of cyclosporine (considering the dose), of which up to 83% was associated with the chylomicrons. 

Kajosaari LI, Niemi M, Neuvonen M, et al. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther 2005 78 388-399. 

The effects of cyclosporin A on the pharmacokinetics of etoposide have been determined and were shown to be dose dependent. A variable range of cyclosporin A concentrations was obtained (297-5073 ng/mL), and it was observed that patients with higher cyclosporin A concentrations also had larger increases in etoposide AUC (290). Results from studies using clinically relevant plasma concentrations of cyclosporin A (1000-5000 ng/mL) as a P-gp inhibitor resulted in mean 48%, 52%, and 52% decreases in the systemic, renal, and nonrenal clearances of intravenously administered etoposide (232,290). Similar decreases in the systemic, renal, and nonrenal clearances of doxorubicin were observed with administration of cyclosporin A (232,291). 

Fluconazole Fluconazole may increase the plasma concentration of phenytoin, sulfonylurea (hypoglycemic), cyclosporin, zidovudine, cisapride, and terfenadine. Coadministration of fluconazole with rifampicin results in the reduced plasma concentration of fluconazole. Griseofulvin may reduce the plasma concentration of salicylates, coumarin, anticoagulants, and oral contraceptives. 

Fig. 5.2 Average plasma concentration versus time profile for cyclosporin A with ( ) and without ( ) AG (720 pg/kg) intraduodenally administered to rats. Data are means of 3-6/group. Adopted from Salama et al. (2005)...

CYP3A4 activity, significantly decreasing plasma concentrations and the pharmacologic effect of a number of agents, including alprazolam, amitriptyline, cyclosporine, indinavir, methadone, nevirapine, simvastatin, tacrolimus, and oral contraceptives (69-77). 

Inhibitors of OATP transport are typically ster-ically bulky compounds, including anions, cations, and neutral compounds (95). Various medications have been shown to interact with OATPs, including HMG CoA reductase inhibitors, cyclosporine, quinidine, rifampin, ketoconazole, verapamil, and certain protease inhibitors. Cyclosporine and rifampin have relatively high ratios of plasma concentration to Ki, suggesting the potential for clinically significant drug-drug interactions via modulation of OATP. On the other hand, plasma concentrations of pravastatin are... 

Interactions. Drugs that lower gastric acidity, e.g. antacids, histamine H2 receptor antagonists, impair the absorption of ketoconazole from the gastrointestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 isoenzymes and thus inhibits the metabolism (and increases effects of) oral anticoagulants, phenytoin and cyclosporin, and increases the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole. 

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