Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys

Abstract

The pharmacokinetics of 2,3-dideoxyadenosine (ddA), didanosine, 2,3-dideoxyguanosine (ddG), and 6-halogenated prodrugs of ddG, 6-chloro-ddG and 6-iodo-ddG, in plasma and cerebrospinal fluid (CSF) were studied in a non-human primate model. ddA was rapidly and completely deaminated to didanosine, such that didanosine concentration profiles in plasma and CSF were identical following administration of ddA and didanosine. The mean clearance of didanosine was 0.50 liters/h/kg, the terminal half-life was 1.8 h, and the CSF-to-plasma ratio was 4.8%. The disposition of ddG was similar, with a clearance of 0.70 liters/h/kg and a half-life of 1.7 h. The adenosine deaminase-mediated conversion of the 6-halogenated-ddG prodrugs to ddG was rapid but incomplete (48% for 6-chloro-ddG and 29% for 6-iodo-ddG). The CSF-to-plasma ratios of ddG with equimolar doses of ddG, 6-chloro-ddG, and 6-iodo-ddG were 8.5, 24, and 17%, respectively, but the actual ddG exposures in CSF (area under the CSF concentration-time curve) were comparable for ddG (12.1 M ⅐ h) and the 6-halogenated-ddG prodrugs (18.8 M ⅐ h for 6-chloro-ddG, 9.3 M ⅐ h for 6-iodo-ddG). 6-Chloro-ddG was not detectable in plasma or CSF, and the CSF-to-plasma ratio of 6-iodo-ddG was 9.4%, so the higher CSF-to-plasma ratios of ddG with the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhanced penetration of the prodrug and subsequent dehalogenation to ddG. The penetration of ddG into CSF exceeds that of didanosine and is enhanced by administration of the 6-halogenated prodrugs, although the mechanism of this enhanced penetration is unclear.The devastating effects of human immunodeficiency virus encephalopathy underscore the importance of finding new antiretroviral agents which penetrate into the central nervous system (CNS) to treat this important component of the disease (7). The currently approved antiretroviral drugs in clinical use are dideoxynucleoside analogs, including zidovudine, zalcitabine, and didanosine (ddI) (3). We previously studied the penetration of a series of dideoxypyrimidine nucleoside analogs into cerebrospinal fluid (CSF) and demonstrated that it ranged from over 20% for zidovudine to less than 5% for zalcitabine and that the degree of penetration into CSF was determined by the nucleobase rather than the alterations to the ribose sugar (5). In addition, in subsequent clinical trials the degree of drug penetration into CSF appeared to correlate with efficacy in treating AIDS dementia (19,20).A number of dideoxypurine (ddP) nucleoside analogs have also demonstrated antiretroviral activity in in vitro screening assays (14,15,17,21), and ddI was recently approved for clinical use. 2Ј,3Ј-Dideoxyadenosine (ddA) has a degree of activity similar to that of ddI, but it is almost instantaneously deaminated to ddI in vivo (9). A series of 6-halogenated 2Ј,3Ј-dideoxyguanosine (ddG) and ddI analogs which act as prodrugs of ddG and ddI are currently in the preclinical phase of drug development. The 6-halo-ddP analogs are more lip...

A sensitive and specific liquid chromatography–mass spectrometry method for determination of metacavir in rat plasma

“…There is no report on the development of the method to detect metacavir, although HPLC methods for the quantitation of the other nucleotide analogs (2 ,3 -dideoxyadenosine, didanosine, 2 ,3 -dideoxyguanosine, etc.) in biological matrices (plasma and cerebrospinal fluid) are available in the literature [10], which uses solid phase extraction technique (SPE) with different cartridges for the extraction of the compound of interest from the biological matrices. However, SPE is generally an expensive and time-consuming process when compared with liquid-liquid extraction (LLE) or protein precipitation techniques.…”

Complexation of antiretroviral nucleosides 2′,3′-dideoxyinosine, 2′,3′-dideoxyadenosine and 2′,3′-dideoxyguanosine with β-cyclodextrin. A 1H NMR study

“…[4][5][6] An important problem focusing a lot of attention in the case of ddN antiretrovirals is proper delivery of drugs to the targeting site e.g. central nervous system 7 or liver. 6 CDs, potent candidates for carrier materials, have not been used in this role with ddNs so far.…”