Preclinical pharmacokinetics of anti-infective agents
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Pharmacokinetics is the characteristic interactions of a drug and the body in terms of its absorption, distribution, metabolism and excretion (ADME). Pharmacokinetic related evaluations have been widely applied as one powerful tool to enhance the information gain and the efficiency of the decision making process during drug development. Preclinical pharmacokinetics refers to all in vivo and in vitro pharmacokinetic evaluations supporting drug development, which plays a major role in candidate compounds screening in early stage of drug development. In this dissertation, preclinical pharmacokinetic evaluations were performed to investigate pharmacokinetic properties of anti-infective agents, including an anti-parasitic agent ((1-Decyl)triphenylphosphonium bromide, dTPP), an anti-tuberculosis agent (Two-(Hydroxymethyl)phenylboronic acid cyclic monoester, OH49) and an anti-viral agent (L-β-5-Bromovinyl-[2-(2’-amino-3’-methtyl-butanoyloxy)methyl]-1, 3-(dioxolanyl) uracil, L-BHDU). Simple, rapid, and sensitive HPLC methods were developed and validated for the quantification of these compounds in plasma and tissues. The in vivo pharmacokinetic and tissue distribution studies of dTPP and OH 49 were performed in mice. These pharmacokinetic studies showed that both dTPP and OH49 have low bioavailability, short elimination half-life, rapid clearance from the plasma and wide tissue distribution. The in vitro stability study showed that L-BHDU is substrate of esterase, which may affect pharmacokinetic profiles of L-BHDU in vivo. These pharmacokinetic study results would offer supportive information for the decision making of further drug development.