HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs.
Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an L-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative L-Phe-Sar dipeptide derivative 74 that gave fourfold improved AUC and eight-fold higher C trough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.
Dasatinib (DST), a tyrosine kinase inhibitor, is a novel anticancer agent and Sitagliptin (STG) is an antidiabetic agent of dipeptidyl peptidase-IV inhibitor class. A novel, sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) based method has been developed for simultaneous monitoring of plasma levels of STG and DST in rat plasma. Both analytes and an internal standard (tolbutamide) were chromatographed on YMC-Pack ODS-AM (50 mm  4.6 mm i.d., 3 mm) using a methanol : 2 mM ammonium acetate binary gradient mobile phase at a flow rate of 1 ml min À1 with a splitter (1 : 1) over a 5 min run time. Detection of analytes was performed on a LC-MS/MS system in multiple reaction monitoring (MRM) mode. The transitions monitored were 488.1 / 401.0, 408.1 / 174.0 and 271.1 / 155.0 for DST, STG and IS, respectively. The method was validated over a concentration range of 5.41-1029.60 ng ml À1 for DST and 5.64-1073.56 ng ml À1 for STG. The lower limit of quantification was 5.41 ng ml À1 and 5.64 ng ml À1 for DST and STG, respectively. Recoveries from spiked controls were >82% for the analytes and the internal standard at all QC levels. The intra-and inter-batch precision and accuracy across four quality control levels met established criteria of US Food and Drug Administration guidelines.This method was successfully applied to monitor the pharmacokinetic profile of both STG and DST in Wistar rats. This method can be applicable for pharmacokinetic drug-drug interaction studies.
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