Metabolism and disposition of clarithromycin in man.
The metabolic fate and pharmacokinetics of clarithromycin following a single 250- or 1200-mg oral dose of 14C-clarithromycin were studied in six healthy adult males. Peak plasma levels of clarithromycin averaged 0.6 microgram/ml after the low dose and 2.7 micrograms/ml after the high dose. The AUC of clarithromycin increased 13-fold, with the 4.8-fold increase in dose, while the plasma half-life increased from 4.4 hr to 11.3 hr. The major metabolite in plasma and urine was the microbiologically active 14-hydroxylated-R epimer of clarithromycin. After 5 days, a mean of 38% of the low dose (18% as clarithromycin) and 46% of the high dose (29% as clarithromycin) was recovered in the urine, with approximately one-third eliminated during the first 24 hr. The nature of the urinary and fecal metabolites revealed the involvement of three metabolic pathways, viz. 1) hydroxylation at the 14-position to form the R and S epimers, 2) N-demethylation, and 3) hydrolysis of the cladinose sugar. Secondary metabolism via these pathways was also evident. The overall recovery of metabolites, but not total radioactivity, decreased 42% after the high dose. The nonlinear pharmacokinetic behavior of clarithromycin and the decrease in metabolite production suggest that clarithromycin metabolism can be saturated at high doses.
Ferrero
J L
JL
Drug Metabolism Department, Abbott Laboratories, Abbott Park, IL 60064-3500.
Bopp
B A
BA
Marsh
K C
KC
Quigley
S C
SC
Johnson
M J
MJ
Anderson
D J
DJ
Lamm
J E
JE
Tolman
K G
KG
Sanders
S W
SW
Cavanaugh
J H
JH
D000328:Adult; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D017291:Clarithromycin; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D005243:Feces / Q000032:analysis; D006207:Half-Life; D006801:Humans; D008297:Male
D004917:Erythromycin; D017291:Clarithromycin