Effect of dipyridamole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects

Hendrix, Craig W.; Flexner, Charles; Szebeni, János; Kuwahara, Steven K.; Pennypacker, Sarah D.; Weinstein, John N.; Lietman, Paul S.

doi:10.1128/aac.38.5.1036

Cited by 9 publications

(4 citation statements)

References 13 publications

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“…Nucleoside transport inhibitors (NTIs) have been shown to have potential therapeutic applications in heart disease, 2,3,4,5,6 inflammatory disease, 7 viral infections, 8,9 and cancer chemotherapy. 10,11,12,13,14,15 The ENT1 transporter, which is the focus of this research, is the major nucleoside transporter in most mammalian tissues, especially heart tissue, 16,17 and appears to be the most relevant NT target for therapeutic exploitation.…”

Section: Introductionmentioning

confidence: 99%

Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity

Zhu

Buolamwini

2008

Bioorganic & Medicinal Chemistry

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Conformationally constrained analogue synthesis was undertaken to aid in pharmacophore mapping and 3D QSAR analysis of nitrobenzylmercaptopurine riboside (NBMPR) congeners as equilibriative nucleoside transporter 1 (ENT1) inhibitors. In our previous study (Zhu et al., J. Med. Chem. 46, 831-837, 2003), novel regioisomeric nitro-1, 2, 3, 4-tetrahydroisoquinoline conformationally constrained analogues of NBMPR were synthesized and evaluated as ENT1 ligands. 7-NO 2 -1, 2, 3, 4-tetrahydroisoquino-2-yl purine riboside was identified as the analogue with the nitro group in the best orientation at the NBMPR binding site of ENT1. In the present study, further conformational constraining was introduced by synthesizing 5′-O, 8-cyclo derivatives. The flow cytometrically determined binding affinities indicated that the additional 5′-O, 8-cyclo constraining was unfavorable for binding to the ENT1 transporter. The structure-activity relationship (SAR) acquired was applied to pharmacophore mapping using the PHASE program. The best pharmacophore hypothesis obtained embodied an anti-conformation with three H-bond acceptors, one hydrophobic center, and two aromatic rings involving the 3′-OH, 4′-oxygen, the NO 2 group, the benzyl phenyl and the imidazole and pyrimidine portions of the purine ring, respectively. A PHASE 3D-QSAR model derived with this pharmacophore yielded an r 2 of 0.916 for four (4) PLS components, and an excellent external test set predictive r 2 of 0.78 for 39 compounds. This pharmacophore was used for molecular alignment in a comparative molecular field analysis (CoMFA) 3D-QSAR study that also afforded a predictive model with external test set validation predictive r 2 of 0.73. Thus, although limited, this study suggests that the bioactive conformation for NBMPR at the ENT1 transporter could be anti. The study has also suggested an ENT1 inhibitory pharmacophore, and established a predictive CoMFA 3D-QSAR model that might be useful for novel ENT1 inhibitor discovery and optimization.

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Section: Introductionmentioning

confidence: 99%

Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity

Zhu

Buolamwini

2008

Bioorganic & Medicinal Chemistry

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“…Rifampin, through induction of hepatic microsomal glucuronaltransferase, increases the metabolic clearance of zidovudine (4), with a resultant decrease in plasma zidovudine levels. The lack of a clinically relevant pharmacokinetic interaction has been demonstrated for several drugs which may often be employed concomitantly with zidovudine, e.g., acetaminophen (2), didanosine (10,19,22,26), zalcitabine (dideoxycytidine) (25), dipyridamole (12), foscarnet (1), naproxen (28), and oxazepam (18). The lack of effect of megestrol acetate on zidovudine pharmacokinetics observed in the present study seemed likely, as zidovudine is eliminated mainly by rapid hepatic metabolism to its 5Ј-O-glucuronide (20), which is subsequently excreted in the urine, while megestrol acetate is eliminated mainly by urinary excretion of the parent compound, likely via glomerular filtration with some passive tubular reabsorption, and to a lesser extent as sulfateand glucuronide-conjugated products of oxidative metabolism (6).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic interaction of megestrol acetate with zidovudine in human immunodeficiency virus-infected patients

Harken

Jiang

Wagner

et al. 1997

Antimicrob Agents Chemother

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This nonrandomized, two-period crossover study was performed to assess whether concomitant administration of megestrol acetate influences the steady-state pharmacokinetics of zidovudine and its inactive 5'-O-glucuronide metabolite. Twelve HIV-positive, asymptomatic male volunteers received a 100-mg oral capsule dose of zidovudine at least 30 min before meals five times a day at 0700, 1100, 1500, 1900, and 2300 h on study days 1 to 3 and a single 100-mg dose at 0700 h on day 4. On days 5 to 17, 800 mg of megestrol acetate, as a 40-mg/ml aqueous suspension, was administered orally immediately before the 0700 h dose of zidovudine. On days 5 to 16, zidovudine was also administered at 1100, 1500, 1900, and 2300 h. Serial blood samples were collected for 12 h after the single 100-mg dose of zidovudine on days 4 and 17; trough samples were also obtained just before the 0700 h dose on days 2 to 4 and 15 to 17. Levels of zidovudine and its glucuronide in plasma were assayed by a validated radioimmunoassay. Statistical analysis of trough plasma level data indicated that steady-state levels of zidovudine and its glucuronide in plasma had been attained when pharmacokinetic assessments were made on days 4 and 17. When megestrol acetate and zidovudine were coadministered for 13 days, differences of -14, -6.5, and -4.6% in mean zidovudine peak concentration and areas under the curve at 0 to 4 and 0 to 12 h, respectively, +22.5% in mean trough concentration, +2.6% in mean plasma half-life, and no change in median time to peak were observed compared to conditions when zidovudine was administered alone; for zidovudine 5'-O-glucuronide the respective differences were -9, -7.3, -4.4, +2.3, and +10% and no change. None of the differences were statistically significant (P > 0.05). Concomitant therapy with megestrol acetate, at the dose employed to treat anorexia, cachexia, or an unexplained, significant weight loss in AIDS patients, did not alter the steady-state pharmacokinetics of zidovudine or its 5'-O-glucuronide metabolite.

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“…After continuous intravenous infusion of zidovudine 0.5 to 1.8 mg/kg in 21 children aged between 14 months and 12 years with HIV infection, the CSF to plasma ratio of zidovudine was 0.24. Although coadministration of zidovudine and ganciclovir should be avoided because of the high rate of hematologic intolerance, no clinically significant changes were seen when zidovudine was administered to patients receiving concomitant cotrimoxazole, [82] levofloxacin, [83] azithromycin, [84] dipyridamole, [85] foscarnet, [86] aciclovir, [87] famciclovir [88] or interferon-α. antimicrobials, sedatives and analgesics); hence, the potential for drug interactions is high.…”

Section: In Childrenmentioning

confidence: 99%

Zidovudine

Bhana¹,

Ormrod²,

Perry³

et al. 2002

Pediatric Drugs

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Zidovudine, as monotherapy or in combination with other antiretroviral agents, remains a first-choice therapy for the prophylaxis of mother-to-child HIV transmission as shown by substantial reductions in transmission rates. Where feasible, the optimal strategy to prevent vertical transmission is to combine drug therapy with Cesarean section delivery and no breast-feeding. In addition, zidovudine in combination with another nucleoside analogue and a protease inhibitor is a first- or second-choice therapy for the treatment of pediatric HIV infection as significant and sustained reductions in viral load have been shown in both plasma and cerebrospinal fluid.

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Effect of dipyridamole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects

Cited by 9 publications

References 13 publications

Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity

Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity

Pharmacokinetic interaction of megestrol acetate with zidovudine in human immunodeficiency virus-infected patients

Zidovudine

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