Amino (Hydroxyethoxymethyl) Purine: A New Well-Absorbed Prodrug of Acyclovir

Selby, P.; Blake, S.; Mbidde, E.K.; Hickmott, E.; Powles, R; Stolle, K; McElwain, T. J.; Whiteman, Paul; Fiddian, A P

doi:10.1016/s0140-6736(84)91624-6

Cited by 45 publications

(6 citation statements)

References 12 publications

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“…Many other investigators have studied prod rugs of acyclovir (Colla et al, 1983;Selby et al, 1984;Welch et al, 1985;Kumar et al, 1988;Bundgaard et al, 1989Bundgaard et al, , 1991Stimac and Kobe, 1990). The work of Colla and colleagues is particularly relevant to this paper.…”

Section: Acyclovirmentioning

confidence: 93%

Amino Acid Ester Prodrugs of Acyclovir

Beauchamp

Orr

Miranda

et al. 1992

Antivir Chem Chemother

203

138

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SummaryEighteen amino acid esters of the antiherpetic drug, acyclovir, were synthesized as potential prodrugs for oral administration. The esters were examined for in vitro antiviral activity against herpes simplex virus Type 1 (HSV-1). They were found to have less potency than the parent compound. Their efficiencies as prodrugs were evaluated in rats by measuring the urinary recovery of acyclovir. Ten prodrugs produced greater amounts of the parent drug in the urine. The L-amino acid esters were better prodrugs than the corresponding D-or D,L-isomers, suggesting the involvement of a stereoselective transporter. The L-valyl ester, 256U87, was the best prodrug. Sixty three per cent of its administered dose was excreted as acyclovir in the urine, a considerable improvement over acyclovir itself, for which this value was 19%. Since 256U87 was stable in aqueous solutions, its conversion to acyclovir in vivo was probably enzyme catalyzed. This L-valyl ester prodrug of acyclovir is now undergoing clinical evaluation.

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Section: Acyclovirmentioning

confidence: 93%

Amino Acid Ester Prodrugs of Acyclovir

Beauchamp

Orr

Miranda

et al. 1992

Antivir Chem Chemother

203

138

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“…In the event, such a pharmaceutical system is not likely to be required because a prodrug with excellent absorptive properties has been developed (6deoxyacyclovir) and has been used in clinical Table 1 Pharmacokinetic parameters and urinary recoveries of acyclovir when given as tablet (n = 9); duodenal infusion (n = 9) and sipped solution (n = 6). Means (Selby et al, 1984). However the study is simple and could be repeated on other drugs with capacity limited absorption to give encouragement or guidance for pharmaceutical development.…”

Section: Discussionmentioning

confidence: 99%

Human gastrointestinal absorption of acyclovir from tablet duodenal infusion and sipped solution.

Lewis¹,

Fowle²,

Bittiner³

et al. 1986

Brit J Clinical Pharma

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On two occasions at least 1 week apart, nine healthy male volunteers were administered in random order either 2 x 200 mg (1.8 mmol) acyclovir tablets or 400 mg of acyclovir in 500 ml of 5% dextrose solution which was infused at constant rate into the duodenum over 4 h. Six of the subjects subsequently sipped the same solution at the rate of 10.4 ml in each 5 min period for 4 h. Blood and urine were sampled over 24 h for each mode of administration. Acyclovir was assayed by radioimmunoassay. Mean areas under the plasma concentrationtime curves (AUCs) + s.d. for tablet (T), intraduodenal infusion (I) and sipping (S) were, respectively: T = 14.7 + 5.1; I = 24.6 + 5.1; S = 28.4 + 9.5 (n = 6) ,umol 1-1 h. AUCs for I and S were significantly greater than that for T (2P < 0.05). Mean apparent maximum plasma concentrations (Cmax) + s.d. were T = 3.8 + 1.5; I = 4.8 + 0.9; S = 5.1 + 1.5 ,umol 1-1. This trend to higher values for I and S was not significant. Mean apparent plasma disappearance half-lives (ttl2) + s.d. were respectively T = 2.3 + 0.4; I = 2.7 + 0.5; S = 3.0 ± 0.2 h, I being significantly greater than T (2P < 0.05), as was S greater than T (2P < 0.01). The mean 24 h urinary recovery + s.d. of acyclovir (n = 8) was T = 309 + 119 ,umol (17% of dose); I = 471 + 83 ,imol (26% of dose); S = 507 ± 180 ,umol (28% of dose). I > T (P < 0.01), S > T (P < 0.05). Acyclovir absorption is increased when contact time of a solution with the absorptive area of the human gut is increased as compared with absorption available from the tablet. This suggests capacity limited absorption.

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“…Acyclovir and its oral prodrug descyclovir are noncyclic guanosine analogues that spe cifically inhibit viral DNA synthesis and hardly interfere with host cell DNA synthesis [50][51][52][53], The acyclic structure of acyclovir implies its effect as a chain terminator of DNA synthesis because it lacks the 3'hydroxyl group essential for DNA elongation. tion transiently, but the difference in HBeAg seroconversion between treated patients and controls did not reach statistical significance (table 2).…”

Section: Acyclovir and Descyclovirmentioning

confidence: 99%