Effect of age on the gastrointestinal absorption of acyclovir in rats.
Drug elimination from the body after intravenous administration of acyclovir (20 mg kg-1) was delayed in 1-week-old rats but the pharmacokinetic data for 2.5-week-old rats were the same as those for 8-week-old rats. The areas under the plasma concentration-time curves at 0-infinity h (AUC) after oral administration of acyclovir (20 mg kg-1) decreased with increasing age. The absolute bioavailabilities for 1-, 2.5-, 3- and 8-week-old rats were 77.59, 51.52, 14.61 and 7.30%, respectively. The gastrointestinal absorption of poorly absorbed acyclovir was good for rats younger than 2.5 weeks but dropped abruptly between 2.5 and 3 weeks of age. The intestinal membrane permeability of acyclovir was studied using the everted sac method. The rate of transfer of an initial concentration of 10 microM acyclovir from the mucosal to the serosal side was constant until 60 min in rats of different ages while the rate in 2.5-week-old rats was significantly greater than that in 3-, 4- and 8-week-old rats. Abrupt in-vivo and in-vitro changes were observed in the experimental results between 2.5- and 3-week-old rats; this period coincided with the weaning period of the rat. The membrane transport mechanism of acyclovir in 2.5- and 8-week-old rats was also studied. Cumulative transferred amounts of acyclovir were linear (r = 0.99) over the range 5 microM-1 mM and dose-independent. The influence of metabolic inhibitors (sodium azide, 2,4-dinitrophenol, ouabain), purine and pyrimidine analogues (2-deoxyguanosine, guanine, adenine, uridine) and temperature on the permeation of acyclovir was studied. The permeation of acyclovir was inhibited only by 2-deoxyguanosine and guanine in 2.5-week-old rats. These results suggest that throughout the maturation period, the gastrointestinal absorption mechanism of acyclovir is predominantly via passive diffusion with little or no active or facilitated transport.(ABSTRACT TRUNCATED AT 250 WORDS)
Fujioka
Y
Y
Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
Mizuno
N
N
Morita
E
E
Motozono
H
H
Takahashi
K
K
Yamanaka
Y
Y
Shinkuma
D
D
D000212:Acyclovir / Q000097:blood / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D005260:Female; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000212:Acyclovir