Use of isotopically chiral [4'-13C]famciclovir and 13C NMR to identify the chiral monoacetylated intermediates in the conversion of famciclovir to penciclovir by human intestinal wall extract.
Famciclovir is the oral form of the potent antiherpesvirus agent, penciclovir. Hydrolysis of one of the acetyl ester groups of famciclovir creates a chiral centre leading to the possible formation of (R)- and (S)-enantiomers. During its conversion to penciclovir, famciclovir forms two chiral metabolites, namely monoacetyl-6-deoxy-penciclovir and monoacetyl-penciclovir. The absolute configuration and stereospecificity of the monoacetyl metabolites of famciclovir, produced in human intestinal wall extract, were determined using isotopically chiral famciclovir and 13C NMR spectroscopy of the isolated metabolites. 13C NMR showed that the esterase(s), in human intestinal wall extract, hydrolysed the acetyl group preferentially from the pro-(S)-acetoxymethyl group of famciclovir. The specificity of esterase action in forming monoacetyl-6-deoxy-penciclovir and monoacetyl-penciclovir was about 77 and 72%, respectively.
Vere Hodge
R A
RA
SmithKline Beecham Pharmaceuticals, Epsom, Surrey, England.
Darlison
S J
SJ
Readshaw
S A
SA
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000107:Acetylation; D000212:Acyclovir / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism*; D001711:Biotransformation; D002247:Carbon Isotopes; D000077595:Famciclovir; D006147:Guanine; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D014020:Tissue Extracts
D000998:Antiviral Agents; D002247:Carbon Isotopes; D011355:Prodrugs; D014020:Tissue Extracts; C053539:penciclovir; D015075:2-Aminopurine; D006147:Guanine; D000077595:Famciclovir; D000212:Acyclovir