Acyclovir (ACV)、阿昔洛韋的介紹

Definition

Acyclovir (ACV) is the key intermediate in the biosynthesis of all penicillins and cephalosporins by eukaryotic and prokaryotic microorganisms.

Discovery

Gnann J W et al., in 1983 studied the mechanism of action, pharmacokinetics and clinical applications of ACV 1. Tadepalli S et al., in 1986 developed a simple and sensitive enzyme-linked immunosorbent assay for the detection and quantitation of ACV in human plasma and urine. ACV immobilized on a solid phase and free acyclovir in the sample solution were allowed to compete for a limited amount of anti-acyclovir monoclonal antibody. The specific antibody bound to the immobilized ACV was detected by the use of alkaline phosphatase conjugated anti-mouse imtnunoglobulin 2. Balzarini J et al., 2002 designed a number of acyclovir and ganciclovir derivatives that are endowed with intrinsic strong fluorescent characteristics by synthesizing tricyclic ACV and GCV derivatives containing an additional aromatic entity attached to the purine system 3.

Structural Characteristics

ACV also referred to as acycloguanosine, demonstrates strong and selective activity against herpes simplex and varicellazoster viruses. ACV structure is [9-(2-hydroxyethoxy)methylguanine] 2.  Tadepalli S et al., in 1986 synthesized 1-O-octadecyl-sn-glycero-3-phospho-acyclovir (ODG-P-ACV), 1-O-hexadecylpropanediol-3-phospho-acyclovir (HDP-P-ACV), and 1-O-octadecyl-sn-glycero-3-phospho-azidothymidine (ODG-P-AZT), and evaluated their antiviral activity in human hepatoma cells that constitutively produce HBV 4. Results from specificity studies showed that there was a high degree of cross-reactivity with ACV and ACV succinate, minor cross-reactivity with the primnary metabolite of ACV (9-carboxymethoxymethylguanine [CMMG]), and significant cross-reactivity with 8-hydroxy-9- (2-hydroxyethoxy)methylguanine (8-OH-ACV), a minor metabolite. 9-(2-14ydroxy-1-hydroxymethylethoxy)methylguanine (BW B759U), structurally similar to ACV, exhibited low but measurable cross-reactivity 2.

Mode of Action

The mechanism of action of ACV and its bioavailability and pharmacokinetics in humans have been established for both intravenous and oral formulations of the drug. ACV triphosphate inhibit the DNA polymerase of human hepatitis B virus (HBV) by 50% at submicromolar concentrations, but no effects of ACV treatment have been noted on the clinical manifestations of hepatitis B. However, HDP-P-ACV and ODG-P-ACV inhibited viral replication by 50% at 0.5 and 6.8 μM, respectively. Based on the EC50, HDP-P-ACV, ODG-P-ACV, and ODG-P-AZT were > 200, > 14.7, and > 48 times more active than their free nucleosides in reducing HBV replication in 2.2.15 cells. To evaluate the biochemical basis for the increased antiviral activity, authors studied the uptake and metabolism of 1-O-octadecyl-sn-glycero-3-phospho-[3H]acyclovir (ODG-P-[3H]ACV) in HepG2 cells. Cellular uptake of ODG-P-[3H]ACV was found to be substantially greater than that of [3H]ACV, and cellular levels of ACV-mono-, -di-, and -triphosphate were much higher with ODG-P-ACV. ODG-P-[3H]ACV was well absorbed orally. Based on urinary recovery of tritium after oral or parenteral administration of the radio labeled compounds, oral absorption of ODG-P-ACV in mice was 100% versus 37% for ACV. ODG-P-ACV plasma area under the curve was more than 7-fold greater than that of ACV. Lipid prodrugs of this type is useful orally in treating viral diseases 4,5,6.

Functions

ACV is an antiviral drug, which selectively inhibits replication of members of the herpes group of DNA viruses with low cell toxicity. This drug is used clinically in treating a variety of herpesvirus infections 7.

Prodrug of ACV, Valaciclovir (VACV), a prodrug of ACV is usually preferred in the oral treatment of viral infections, mainly herpes simplex virus (HSV).

A number of tricyclic ACV and ganciclovir (GCV) derivatives substituted with bulky lipophilic groups have been identified as potent and highly selective cytostatic agents against herpes simplex virus type 1 (HSV-1)-thymidine kinase (TK) gene-transduced human osteosarcoma and murine mammary carcinoma tumor cells.

Effect in cell culture, the tricyclic ACV derivatives were also endowed with a very pronounced bystander effect in cell culture, albeit at relatively high drug concentrations.

ACV acts against cytomegalovirus (CMV) in general and the latter against CMV retinitis mainly via phosphorylation and inhibition of the viral DNA polymerase 8.

References

1.     Gnann JW Jr, Barton NH, Whitley RJ (1983). Acyclovir: mechanism of action, pharmacokinetics. Safety and clinical applications. Pharmacotherapy, 3(5):275-285.

2.     Tadepalli SM, Quinn RP, Averett DR (1986). A competitive enzyme-linked immunosorbent assay to quantitate acyclovir and BW B759U in human plasma and urine. Antimicrob Agents Chemother., 29(1):93-98.

3.     Balzarini J, Ostrowski T, Goslinski T, De Clercq E, Golankiewicz B (2002). Pronounced cytostatic activity and bystander effect of a novel series of fluorescent tricyclic acyclovir and ganciclovir derivatives in herpes simplex virus thymidine kinase gene-transduced tumor cell lines. Gene Therapy., 9(17):1173-1182.

4.     Hostetler KY, Beadle JR, Kini GD, Gardner MF, Wright KN, Wu TH, Korba BA (1997). Enhanced oral absorption and antiviral activity of 1-O-octadecyl-sn-glycero-3-phospho-acyclovir and related compounds in hepatitis B virus infection, in vitro. Biochemical pharmacology, 53(12):1815-1822.

5.     Elion GB (1982). Mechanism of action and selectivity of acyclovir. Am. J. Med., 73(1A):7-13.

6.     De Miranda P, Blum MR (1983). Pharmacokinetics of acyclovir after intravenous and oral administration. J. Antimicrob. Chemother., 12:29-37.

7.     Blum MR, Liao SH, de Miranda P (1982). Overview of acyclovir: pharmacokinetic disposition in adults and children. Am. J. Med., 73:186-192.

8.     Loregian A, Gatti R, Palù G, De Palo EF (2001). Separation methods for acyclovir and related antiviral compounds. J Chromatogr B Biomed Sci Appl., 764(1-2):289-311.