Lansoprazole‐sulfide, pharmacokinetics of this promising anti‐tuberculous agent

Sipho Mdanda, Sooraj Baijnath, Adeola Shobo, Sanil D. Singh, Glenn E.M. Maguire, Hendrik G. Kruger, Per I. Arvidsson, Tricia Naicker, Thavendran Govender

Lansoprazole (LPZ) is a commercially available proton-pump inhibitor (PPI) whose primary metabolite, lansoprazole sulphide (LPZS) was recently reported to have in vitro and in vivo activity against M. tb. It was also reported that a 300 mg kg(-1) oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates, was developed. We administered 15 mg kg(-1) oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high amounts of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL(-1) respectively, which were significantly greater than its MIC for M. tb. While oral and i.p. administration of LPZ resulted in significant amounts of it in the lung, it does not undergo sufficient cellular conversion to its anti-TB metabolite. However, when LPZS itself is administered i.p., significant amounts penetrate the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an antiTB compound.