RESUMO
The objectives of this article were to review the mechanism and clinical significance of statins-macrolides interaction, determine which combination has the highest risk for the interaction, and identify key patients' risk factors for the interaction in relation to the development of muscle toxicity. A literature review was conducted in PubMed and Embase (1946 to December 2018) using combined terms: statins - as group and individual agents, macrolides - as group and individual agents, drug interaction, muscle toxicity, rhabdomyolysis, CYP3A4 inhibitors, and OAT1B inhibitors, with forward and backward citation tracking. Relevant English language in vivo studies in healthy volunteers, case reports, and population studies were included. The interaction between statins and macrolides depends on the type of statin and macrolide used. The mechanism of the interaction is due to macrolides' inhibition of CYP3A4 isoenzyme and OAT1B transporter causing increased exposure to statins. The correlation of this increased statin's exposure to the development of muscle toxicity could not be established, unless the patient had other risk factors such as advanced age, cardiovascular diseases, renal impairment, diabetes, and the concomitant use of other CYP3A4 inhibitors. Simvastatin, lovastatin, and to lesser extent atorvastatin are the statins most affected by this interaction. Rosuvastatin, fluvastatin, and pravastatin are not significantly affected by this interaction. Telithromycin, clarithromycin, and erythromycin are the most "offending" macrolides, while azithromycin appears to be safe to use with statins. This review presented a clear description of the clinical significance of this interaction in real practice. Also, it provided health care professionals with clear suggestions and recommendations on how to overcome this interaction. In conclusion, understanding the different characteristics of each statin and macrolide, as well as key patients' risk factors, will enable health care providers to utilize both groups effectively without compromising patient safety.
RESUMO
BACKGROUND: The drug delivery characteristics of each inhaler/spacer combination are unique. The spacer size as well as the presence of electrostatic charge greatly influence the inhaler dose emission and in vivo delivery. Using a previously developed urinary pharmacokinetic method, we have measured the relative lung and systemic bioavailability of beclometasone dipropionate (BDP) after inhalation from 2 hydrofluroalkane-beclometasone dipropionate (HFA-BDP) formulations when used with a spacer. METHODS: 12 healthy volunteers received 8 randomized doses, separated by 7 d, of inhaled of BDP with either the Clenil pressurized metered-dose inhaler (pMDI; 250 µg) or the breath-actuated Qvar Easi-Breathe inhaler (100 µg), used alone or with a spacer. The urinary amounts of BDP excreted and retained in the spacer were assayed using a liquid chromatographic mass spectrometer. The spacer was assessed after washing with a detergent solution that was either rinsed or not rinsed with water. In addition, the aerodynamic characterization of each inhaler/spacer combination was assessed using the Andersen Cascade Impactor operated at 28 L/min using a 4-L inhalation volume. The amount of BDP deposited in the induction port, spacer, and various Anderson Cascade Impactor stages were determined. RESULTS: The in vivo 30-min urinary excretion and the in vitro fine particle dose results were only slightly affected by adding the spacer to the Clenil pMDI or the Qvar Easi-Breathe inhaler. However, the spacer significantly reduced drug particle impaction in the oropharynx and minimized deposition in the gastrointestinal tract. Therefore, using spacers with BDP inhalers is associated with a more favorable therapeutic ratio because it has little effect on lung dose, but it significantly reduced throat deposition. An improved lung deposition was achieved with non-rinsed spacers compared to spacers rinsed with water. CONCLUSION: The difference in the BDP particle size between formulations as well as spacer size greatly affected drug deposition in different regions of the respiratory tract.