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Preclinical Development of Inhalable d-Cycloserine and Ethionamide To Overcome Pharmacokinetic Interaction and Enhance Efficacy against Mycobacterium tuberculosis.

ABSTRACT: We compared the pharmacokinetics and efficacy of a combination of d-cycloserine (DCS) and ethionamide (ETO) via oral and inhalation routes in mice. The plasma half-life (t _1/2) of oral ETO at a human-equivalent dose decreased from 4.63?±?0.61 h to 1.64?±?0.40 h when DCS was coadministered. The area under the concentration-time curve from 0 h to time t (AUC_0- _t ) was reduced to one-third. Inhalation overcame the interaction. Inhalation, but not oral doses, reduced the lung CFU/g of Mycobacterium tuberculosis H37Rv from 6 to 3 log₁₀ in 4 weeks, indicating bactericidal activity.

SUBMITTER: Ranjan R

PROVIDER: S-EPMC6535545 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Preclinical Development of Inhalable d-Cycloserine and Ethionamide To Overcome Pharmacokinetic Interaction and Enhance Efficacy against Mycobacterium tuberculosis.

Ranjan Rajeev R Srivastava Ashish A Bharti Reena R Roy Trisha T Verma Sonia S Ray Lipika L Misra Amit A

Antimicrobial agents and chemotherapy 20190524 6

We compared the pharmacokinetics and efficacy of a combination of d-cycloserine (DCS) and ethionamide (ETO) via oral and inhalation routes in mice. The plasma half-life (t1/2) of oral ETO at a human-equivalent dose decreased from 4.63 ± 0.61 h to 1.64 ± 0.40 h when DCS was coadministered. The area under the concentration-time curve from 0 h to time t (AUC0-t ) was reduced to one-third. Inhalation overcame the interaction. Inhalation, but not ...[more]

PMID: 30962335

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