Identification of drugs inhibiting the <i>in vitro</i> metabolism of tacrolimus by human liver microsomes

Christians, Uwe; Schmidt, Gudrun; Bader, Augustinus; Lampen, A.; Schottmann, Renate; Linck, A; Sewing, Karl–Friedrich

doi:10.1111/j.1365-2125.1996.tb00181.x

Cited by 57 publications

(26 citation statements)

References 4 publications

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“…as an inhibitor in an in vitro study is not necessarily an inhibitor in the in vivo situation, drugs that fail to inhibit Omeprazole, a substrate of CYP2C19 [17,19,35], inhibited the 3-hydroxylation of quinine with a mean IC 50 the metabolism of a substrate in vitro will not be inhibitors in vivo [45]. Thus, antimalarial drugs such as chloroquine, value of 18 mm ( Table 1).…”

Section: Inhibition Experimentsmentioning

confidence: 99%

Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes

Zhao

Ishizaki

1997

Brit J Clinical Pharma

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Aims Nine antimalarial ( plus two metabolites of proguanil ) and twelve nonantimalarial drugs were tested for their possible interaction with CYP3A4-catalysed 3-hydroxylation of quinine by human liver microsomes in vitro. Methods 3-Hydroxyquinine was assayed in the incubation mixture by an h.p.l.c. method using fluorometric detection. The respective IC 50 values were estimated for the twenty-one drugs and two metabolites of proguanil tested herein. Results Thirteen drugs exhibited an inhibitory effect on the 3-hydroxylation of quinine. According to the respective mean IC 50 values, the inhibitory rank order of the drugs was: ketoconazole>troleandomycin (TAO, with preincubation)> doxycycline>omeprazole>primaquine>tetracycline=TAO (without preincubation)>nifedipine>erythromycin>verapamil>cimetidine>diltiazem>oleando-mycin>hydralazine. Other drugs or metabolites showed little or no inhibition of quinine metabolism (mean IC 50 >200 or 500 mm). Among the antimalarial drugs, doxycycline showed relatively potent inhibition of quinine 3-hydroxylation with a mean IC 50 value of 17 mm, followed by primaquine and tetracycline, with mean IC 50 values of 20 and 29 mm, respectively. Conclusions When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, TAO and erythromycin are likely to be inhibitors of quinine metabolism in patients when the drugs are co-administrated with quinine.

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Section: Inhibition Experimentsmentioning

confidence: 99%

Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes

Zhao

Ishizaki

1997

Brit J Clinical Pharma

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“…Peyronneau et al (7) reported that liver microsomes from rats pretreated with dexamethasone, a specific inducer of P450 3A, were found to be particularly active for the hydroxylation of the ergot alkaloid bromocriptine, which occurs at the level of its tripeptide moiety. Christians et al (8) identified bromocriptine and ergotamine as inhibitors of the in vitro metabolism of tacrolimus which are metabolized by enzymes of the cytochrome P450 3A subfamily by human liver microsomes. Cytochrome P450 3A is an enzyme system that constitutes a superfamily of heme-thiolate proteins that catalyze the primary oxidation of endogenous substrate and exogenous compounds like drugs and toxin.…”

mentioning

confidence: 99%

Hepatic Metabolism of Ergot Alkaloids in Beef Cattle by Cytochrome P450

Moubarak

Rosenkrans

2000

Biochemical and Biophysical Research Communications

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“…One possible explanation is that since FK and NSAIDs have high binding affinity to plasma protein, there might be a competition between the two drugs, with an increase of free FK, favoring its metabolism by the hepatic cytochrome system [37, 38]. …”

Section: Discussionmentioning

confidence: 99%

Tacrolimus and Nonsteroidal Anti-Inflammatory Drugs: An Association to Be Avoided

et al. 2005

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Background: Tacrolimus (FK) and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute nephrotoxicity. The expanding use of tacrolimus and the intense consumption of NSAIDS increase the chances of their simultaneous use. Methods: Rats receiving a nonselective COX inhibitor (diclofenac, D) and FK or a selective COX-2 inhibitor (rofecoxib, RO) and FK were treated with FK (2 mg/kg/day), D (10 mg/kg/day), RO (3 mg/kg/day), FK+D, FK+RO and vehicle for 7 days on low-salt diet. Results: Both associations significantly impaired glomerular filtration rate (GFR; 0.63 ± 0.06 ml/min/100 g in FK+D, 0.83 ± 0.06 ml/min/100 g in FK+RO) which did not occur with single drug therapy (0.98 ± 0.03 ml/min/100 g in D, 1.06 ± 0.04 ml/min/100 g in RO, 0.99 ± 0.05 ml/min/ 100 g in FK) or vehicle (1.10 ± 0.05 ml/min/100 g). GFR decrease was significantly higher with FK+D. GFR impairment occurred without RBF or RVR major changes. Mild tubular vacuolization and dilatation and acute degenerative changes were observed in tubular cells. FK+D animals showed a marked weight loss, not observed in the other groups. FK+NSAIDs association decreased FK blood levels (1.73 ± 0.3 ng/ml in FK+D, 1.8 ± 0.3 ng/ml in FK+RO, 3.2 ± 0.4 ng/ml in FK, p < 0.05). Conclusions: The association of FK and nonselective or COX-2 selective NSAIDs in salt-depleted animals caused a significant GFR impairment and decreased FK blood levels.

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Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes

Cited by 57 publications

References 4 publications

Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes

Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes

Hepatic Metabolism of Ergot Alkaloids in Beef Cattle by Cytochrome P450

Tacrolimus and Nonsteroidal Anti-Inflammatory Drugs: An Association to Be Avoided

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