Predicting Interactions between Rifampin and Antihypertensive Drugs Using the Biopharmaceutics Drug Disposition Classification System

Study Objective Lack of blood pressure control is often seen in hypertensive patients concomitantly taking antituberculosis medications due to the complex drug-drug interactions between rifampin and antihypertensive drugs. Therefore, it is of clinical importance to understand the underlying mechanisms of these interactions to help formulate recommendations on the use of antihypertensive drugs in patients taking these medications concomitantly. Our objective was to assess the reliability of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to predict potential interactions between rifampin and antihypertensive drugs and thus provide recommendations on the choice of antihypertensive drugs in patients receiving rifampin. Design Evidence-based in vitro and in vivo predictions of drug-drug interactions. Measurements and Main Results We systematically evaluated interactions between rifampin and antihypertensive drugs using the theory of the BDDCS, taking into consideration the role of drug transporters and metabolic enzymes involved in these interactions. We provide recommendations on the selection of antihypertensive drugs for patients with tuberculosis. Antihypertensive drugs approved by the U.S. Food and Drug Administration and the China National Medical Products Administration were included in this study. The drugs were classified into four categories under the BDDCS classification. Detailed information on cytochrome P450 (CYP) enzymes and drug transporters for each antihypertensive drug was searched in PubMed and other electronic databases. This information was combined with the effects of rifampin on CYP enzymes and drug transporters, and the direction and relative extent of the potential interactions between rifampin and antihypertensive drugs were predicted. Recommendations were then made using the theory of BDDCS. A thorough systematic literature review was performed, and data from all published human studies and case reports were summarized for the validation of our predictions. Interventional and observational studies published in PubMed and two Chinese databases (CNKI and WanFang) through December 16, 2019, were included, and data were extracted for validation of the predictions. Using the BDDCS theory, class 3 active drugs were predicted to exhibit minimal interactions with rifampin. On reviewing case reports and pre-post studies, the predictions we made were found to be reliable. When antituberculosis medications that include rifampin are started in patients with hypertension, it is recommended that the use of calcium channel blockers and classes 1 and 2 beta-blockers be avoided. Angiotensin-converting enzyme inhibitors, olmesartan, class 3 beta-blockers, spironolactone, and hydrochlorothiazide would be preferable because clinically relevant interactions would not be expected. Conclusion Application of the BDDCS to predict interactions between rifampin and antihypertensive drugs for patients with both tuberculosis and hypertension was found to be reliable. It should be noted, however, that based on the CYP enzyme and drug transporter information we reviewed, the mechanisms of all of the interactions could not be elucidated, and the predictions are only based on theory. The real effects of rifampin on antihypertensive drugs need to be further observed. More studies in both animals and humans are needed in the future.