Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue

Abstract

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and LAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.

Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 observed during zidovudine (AZT) therapy

“…In addition to mutations previously associated with zidovudine resistance, three sequences contained the mutation 215 ~hr~Asp, the phenotype of which is unknown. Zidovudine sensitive genotypes persisted in the brain of this patient, and this might suggest that zidovudine did not reach inhibitory concentrations within this organ due to restricted transport across the blood brain barrier or from the cerebro-spinal fluid to the brain (Klecker et al, 1987;Terasaki & Pardridge, 1988;Lupia et al, 1993). The presence of zidovudine resistant genotypes in the cerebro-spinal fluid has been reported (di Stefano et al, 1993), although at present it is not clear whether this population is representative of that found in the brain.…”

Interactions of the Dipeptide Ester Prodrugs of Acyclovir with the Intestinal Oligopeptide Transporter: Competitive Inhibition of Glycylsarcosine Transport in Human Intestinal Cell Line-Caco-2

“…After oral and topical administration, VACV is rapidly and completely converted in vivo by enzymatic hydrolysis to acyclovir, the active parent drug. VACV has been reported to increase the oral bioavailability of acyclovir 3-to 5-fold in humans (Beauchamp et al, 1992;Lupia et al, 1993;Weller et al, 1993). Enhanced oral (Balimane et al, 1998;de Vrueh et al, 1998;Han et al, 1998b) and ocular (Anand and Mitra, 2002) absorption of acyclovir after administration of valacyclovir have been attributed to the hPEPT1-mediated translocation of the amino acid prodrug.…”

“…Small dipeptides, angiotensin-converting enzyme inhibitors, and ␤-lactam antibiotics are known substrates for intestinal PEPT1 (Dantzig and Bergin, 1990;Hashimoto et al, 1994;Ganapathy et al, 1995;Han et al, 1998a;Inui et al, 2000). Strategies have been used to design prodrugs of various poorly absorbed drugs targeted toward receptors/transporters for improved bioavailability (Lupia et al, 1993;Weller et al, 1993;Guo and Lee, 1999;Sakaeda et al, 2001;Anand et al, 2002a;Manfredini et al, 2002).…”

Enhanced delivery of ganciclovir to the brain through the use of redox targeting

“…While a variety of targetors have been examined, derivatives of the dihydronicotinate-nicotinate redox couple have proven to be the most successful. Application of the approach to a number of drugs, including antiviral nucleosides, has been reported (1,4,7,9,10,24,25).…”