Background Recent studies have identified the ‘triple whammy’ in which combinations of diuretics, nonsteroidal anti‐inflammatory drugs (NSAIDs), ACE inhibitors (ACEI) and/or angiotensin receptor antagonists (ARA) may impair renal function. Methods We performed a cross‐sectional study of patients admitted to a general medical ward of a teaching hospital. Age, sex, disease status and prior consumption of the ‘target’ drugs, diuretics, NSAIDs (including aspirin), ACEI and ARA were correlated with creatinine and creatinine clearance on admission. Results Three hundred and one patients (48% male) were included, 135 were on no prior target drugs, 87 on one, 60 on two and 19 on three such drugs. There was a significant (P < 0.01) correlation between both creatinine and creatinine clearance with male sex, age and number of target drugs. Multivariate analysis confirmed these associations but did not support associations between renal function and heart failure or total number of diagnoses. Increasing doses of diuretics, possibly because in many cases this included two drugs, but not the other drugs, were significantly (P < 0.001) associated with impaired renal function. For the other three drug groups patients on doses of any drug at lower than the defined daily dose (DDD) did not have significantly different creatinine or creatinine clearance from those on doses at or above the DDD. Conclusion Taking two or more of the identified drugs was associated with significant renal impairment but did not correlate with heart failure or other diseases for which the drugs might have been prescribed. Care is necessary to balance the demonstrated advantages of these medications against the risk of inducing renal failure.
Rifampin significantly induces CYP2B6 activity in vivo, and the clinical consequences of potential interactions between rifampin and CYP2B6 substrates deserve further investigation. Rifampin appears to induce the elimination of hydroxybupropion. Differences in bupropion pharmacokinetics that were observed between white subjects and Chinese subjects can be attributed to differences in body weight, suggesting that, for a given subject weight, CYP2B6 activity is similar in white subjects and Chinese subjects.
A sensitive and stereoselective assay has been developed for the quantitation of the enantiomers of hydroxybupropion, an active metabolite of bupropion, in human plasma. The assay used liquid-liquid extraction and a Cyclobond I 2000 HPLC column with a mobile phase containing 3% acetonitrile, 0.5% triethylamine, and 20 mM ammonium acetate (pH 3.8). The technique was linear over the concentration range of 12.5-500 ng/ml for (2R,3R)- and (2S,3S)-hydroxybupropion. The method was reproducible as both interday and intraday variabilities were less than 10% for both hydroxybupropion enantiomers. Overall extraction recovery of hydroxybupropion enantiomers and the internal standard phenacetin from plasma was greater than 80% and reproducible over the concentration range of 12.5-500 ng/ml for each enantiomer. The limit of quantification (LOQ) of hydroxybupropion enantiomers was 12.5 ng/ml. The stereoselective pharmacokinetics of both (2R,3R)- and (2S,3S)-hydroxybupropion in healthy male subjects (n = 16) were investigated after a single dose of (rac)-bupropion either alone or during rifampicin administration. (2R,3R)-Hydroxybupropion was the predominant enantiomer present in plasma. A stereoselective effect of rifampicin on hydroxybupropion concentrations was observed, with rifampicin influencing the pharmacokinetics of each hydroxybupropion enantiomer in a different manner. The ratio of (2R,3R)-hydroxybupropion (AUC(0-24)) to (2S,3S)-hydroxybupropion (AUC(0-24)) increased from 4.9 +/- 1.6 to 8.3 +/- 1.9 during rifampicin administration (P < 0.001). A time-dependent change in the hydroxybupropion enantiomeric ratio was observed after (rac)-bupropion administration both before and during rifampicin coadministration, with an increase in the relative proportion of (2S,3S)-hydroxybupropion over the 24 h postdose period.
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