Pharmacokinetics of cimetidine during lactation: species differences in cimetidine transport into rat and rabbit milk.
The disposition of cimetidine, including transfer into milk, was characterized in the rabbits and rats. Nursing rabbits and suckling offspring exhibited similar pharmacokinetics with a mean systemic disease (CL) in the adults and pups of 22.0 +/- 5.2 and 30.4 +/- 8.9 ml/min/kg, respectively. Cimetidine exhibited a distributional time lag and a prolonged T 1/2 in milk compared to serum (70 +/- 15 vs. 33 +/- 5 min), resulting in a time-dependent milk to serum (M/S) drug concentration ratio. The ratio of the area under the time curve of cimetidine in serum and milk was 1.49 +/- 0.37 and was comparable to a diffusional model predicted M/S ratio of 1.16 +/- 0.11. Unbound CL after a high cimetidine infusion regimen (16.6 +/- 7.3 ml/min/kg) was significantly less than that after two lower infusion rates (26.2 +/- 4.9 and 29.4 +/- 12.3 ml/min/kg, respectively). M/S determined at increasing steady-state serum concentrations were 1.03, 1.08 and 1.08, respectively, which agreed well with the corresponding predicted M/S (1.06, 1.14 and 1.13, respectively). Cimetidine was also administered to lactating rats and resulted in a concentration-dependent decrease in CL (11.2 +/- 1.5, 10.8 +/- 2.7 and 7.30 +/- 1.0 ml/min, respectively) after three increasing infusion rates. The steady-state M/S ratio decreased slightly from 31.9 +/- 9.0 to 26.5 +/- 9.5 and 24.6 +/- 6.4 with the increasing infusion rate. Steady-state M/S values were 6-fold higher than the predicted M/S value (4.19). Hence, cimetidine transport into rabbit milk appears to be governed by diffusion, whereas cimetidine transfer into rat milk may involve active transport.
McNamara
P J
PJ
Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington.
Burgio
D
D
Yoo
S D
SD
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D002927:Cimetidine / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D007774:Lactation / Q000378:metabolism*; D008892:Milk / Q000032:analysis*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D002927:Cimetidine