Didanosine

Shelton, Mark J.; O’Donnell, Alice; Morse, Gene D.

doi:10.1177/106002809202600511

Cited by 48 publications

(19 citation statements)

References 43 publications

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“…After intravenous administration of dideoxyinosine, the fraction of the dose excreted unchanged in the urine approximates the fraction that is metabolized (9). Although not all of the metabolic pathways of dideoxyinosine have been elucidated, dideoxyinosine is metabolized to hypoxanthine and uric acid (18). Given the potential use of dideoxyinosine in HIV-infected infants and children, with treatment starting at an early stage after birth, it is important to determine whether the pharmacokinetics of dideoxyinosine change significantly with age.…”

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confidence: 99%

Pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques

Pereira

Nosbisch

Unadkat

1994

Antimicrob Agents Chemother

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To determine whether age affects the pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques (Macaca nemestrina), dideoxyinosine (10 mg/kg of body weight) was administered as a single intravenous bolus to macaques at ages <1 week, 1 month, and 4 months. Clearance from plasma at <1 week of age was significantly lower (P < 0.05) and the terminal half-life was significantly higher than the corresponding values obtained at 1 month and 4 months of age. Our data indicate that the pharmacokinetics of dideoxyinosine change significantly with age in M. nemestrina.The incidence of infection with the human immunodeficiency virus (HIV) is on the rise among women of childbearing age. As a result of the maternal-fetal transmission of HIV, the incidence of HIV infection among neonates and children is also on the rise. By 1990, AIDS was one of the 10 leading causes of death among children (16).The dideoxynucleoside analog dideoxyinosine (2',3'-dideoxyinosine; didanosine) is being used in the treatment of HIV infection. However, the question of possible age-dependent changes in the pharmacokinetics of dideoxyinosine in neonates has not been adequately addressed. Balis et al. (2) found no difference between the pharmacokinetics of dideoxyinosine in children (age range, 8 months to 18 years; median, 7.4 years) and adults. After intravenous administration of dideoxyinosine, the fraction of the dose excreted unchanged in the urine approximates the fraction that is metabolized (9). Although not all of the metabolic pathways of dideoxyinosine have been elucidated, dideoxyinosine is metabolized to hypoxanthine and uric acid (18). Given the potential use of dideoxyinosine in HIV-infected infants and children, with treatment starting at an early stage after birth, it is important to determine whether the pharmacokinetics of dideoxyinosine change significantly with age. This information would help to ensure the use of adequate treatment regimens in infants and children and minimize the risk of drug toxicity. Therefore, as part of an ongoing series of investigations on the pharmacokinetics of antiretroviral dideoxynucleosides, we studied the effect of age on the pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques (Macaca nemestrina).Previous studies in our laboratory have indicated that M. nemestrina is an excellent model to use in studying the dispositions of dideoxynucleosides. For example, the pharmacokinetics, including the metabolic and renal clearances of dideoxyinosine (17) and zidovudine (12), in adult macaques, have been shown to be similar to those in humans. In addition, the age-dependent changes in the pharmacokinetics of zidovudine in human infants (3) are similar to those previously reported by us in M. nemestrina (13). MATERIALS AND METHODSDideoxyinosine was supplied by the National Institute of Allergy and Infectious Diseases (Developmental Therapeutics * Corresponding author.Branch, Division of AIDS). All other chemicals used were of reagent grade.Animals. Infant M. nemestrina were serially studied ...

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Pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques

Pereira

Nosbisch

Unadkat

1994

Antimicrob Agents Chemother

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“…In this short review special attention will be paid to possibly altered pharmacokinetics in special circumstances, such as hepatic and renal dysfunction, pregnancy, stage of disease, etc The relevance of therapeutic drug moni toring of antiretroviral agents to support the pharma cotherapy of patients with HIV infection is discussed at the end of this review. Related reviews on this sub ject can be found in the literature [7][8][9][10][11][12], A summary of the pharmacokinetic parameters of the three drugs is presented in Table 1. A review of possible drug-drug interactions involving antiretroviral agents will be the subject of a forthcoming paper.…”

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confidence: 99%

Concise overview of the clinical pharmacokinetics of dideoxynucleoside antiretroviral agents

1995

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In this paper aspects of the clinical pharmacokinetics of the antiretroviral agents zidovudine, didanosine and zalcitabine are reviewed. Special attention is paid to possibly altered pharmacokinetics in special circumstances, such as hepatic and renal dysfunction, pregnancy, stage of disease, etc, The dideoxynucleoside antiretroviral agents have some clinical pharmacokinetic properties in common (rapid absorption and elimination), but substantial differences exist in their degree of absorption, metabolism and penetration into the cerebrospinal fluid. All agents display wide interpatient variability in pharmacokinetic parameters. The relevance of therapeutic drug monitoring of antiretroviral agents is also discussed.

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“…3 However, because of the short biological halflife (about 1 h) of these drugs, 4 conventional oral or iv routes are inherently limited in that they cannot maintain a constant plasma level within the target therapeutic range for a prolonged duration. Moreover, DDI and AZT have low oral bioavailability due to a rapid hepatic "first-pass" metabolism [4][5][6] which requires frequent high dose administration to maintain therapeutic level. Especially, DDI has only 20-40% oral bioavailability 4,6 because it is also susceptible to the acid hydrolysis in the stomach after oral administration.…”

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confidence: 99%

“…Moreover, DDI and AZT have low oral bioavailability due to a rapid hepatic "first-pass" metabolism [4][5][6] which requires frequent high dose administration to maintain therapeutic level. Especially, DDI has only 20-40% oral bioavailability 4,6 because it is also susceptible to the acid hydrolysis in the stomach after oral administration. 6 Several dose-dependent toxic side effects 4,7,8 resulting from excessive systemic concentration after iv or oral administration often require dosage reduction or even cessation of treatment.…”

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Transdermal Delivery of Dideoxynucleoside-Type Anti-HIV Drugs. 2. The Effect of Vehicle and Enhancer on Skin Permeation

Kim¹,

Chien²

1996

Journal of Pharmaceutical Sciences

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The effects of vehicles and enhancers on the skin permeation of the dideoxynucleoside-type anti-HIV drugs Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT) were studied using hairless rat skin at 37 degrees C. After each drug was saturated in various volume fractions of ethanol (EtOH)/water or EtOH/tricaprylin (TCP) cosolvent system for 48 h at 37 degrees C, an in vitro skin permeation study was conducted using Valia-Chien permeation cells for 30 h. The skin permeation rates of DDC, DDI, and AZT from both EtOH/water and EtOH/TCP cosolvent systems increased as the volume fraction of ethanol was increased, reached maximum values at 50-60% (v/v) of ethanol, and then decreased with further increase of ethanol volume fraction. The EtOH/water cosolvent system seems to enhance the skin permeation of these drugs by increasing both the solubility of drug in the vehicles and partitioning of drug into the skin. The skin permeation enhancing effect of EtOH/TCP seems to be solely due to the increase in partitioning of drug into the skin. Addition of 1.0% (v/v) of permeation enhancers, such as oleic acid (OA) and N-methyl-2-pyrrolidone (NMP), in the EtOH/TCP (50:50) cosolvent system could not significantly increase the permeation rate of these drugs. Incorporation of viscous TCP into ethanol probably reduced the thermodynamic activity of enhancers to distribute from the vehicle to the skin. However, incorporation of 1.0% (v/v) of OA in the EtOH/water (60:40) cosolvent system dramatically enhanced the skin permeation of these drugs while reducing the lag time. The permeation rates of these drugs increased as OA concentration was increased up to 0.3% (v/v) in the EtOH/water (60:40) cosolvent system and reached a plateau with further addition of OA. Using a saturated solution in the EtOH/water (60:40) cosolvent system containing 1.0% (v/v) OA, DDC, and AZT reached the target permeation rate required to maintain a therapeutic system level across hairless rat skin. Although only DDC reached the target permeation rate across human cadaver skin, these results suggest that the mutual enhancement effect of ethanol and OA may make transdermal delivery of dideoxynucleoside-type anti-HIV drugs feasible.

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Didanosine

Abstract: Didanosine has demonstrated preliminary efficacy in the treatment of late-stage HIV infection; however, its effect on patient survival, its efficacy relative to ZDV, and its utility in combination with other agents are still under evaluation.

Cited by 48 publications

References 43 publications

Pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques

Pharmacokinetics of dideoxyinosine in neonatal pigtailed macaques

Concise overview of the clinical pharmacokinetics of dideoxynucleoside antiretroviral agents

Transdermal Delivery of Dideoxynucleoside-Type Anti-HIV Drugs. 2. The Effect of Vehicle and Enhancer on Skin Permeation

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