Pharmacokinetics of caffeine and its demethylated metabolites in lactating adult rabbits and neonatal offspring. Predictions of breast milk to serum concentration ratios.

The purpose of this study was to assess the pharmacokinetics of caffeine and its metabolites in the lactating rabbit and suckling pup. The ability of a diffusional model to predict milk-to-serum drug concentration ratios (M/S) observed in vivo from in vitro experiments was established. The distribution into milk of caffeine, paraxanthine, theobromine, and theophylline was measured in lactating New Zealand White rabbits following an iv bolus dose of caffeine (5 mg/kg). M/S ratios were determined in vivo (M/Sobs; caffeine = 0.875 +/- 0.052; paraxanthine = 0.358 +/- 0.019; theobromine = 0.829 +/- 0.038; and theophylline = 0.412 +/- 0.054) under single dose conditions using area under the milk and serum concentration-time profiles. Predicted M/S values (M/Spred; caffeine = 0.797 +/- 0.040; paraxanthine = 0.316 +/- 0.029; theobromine = 0.692 +/- 0.062; and theophylline = 0.385 +/- 0.039) were calculated from in vitro measurements of the unbound fractions of drug in skim milk and serum (fm and fs, respectively), the skim-to-whole milk drug concentration ratio (S/W), milk and serum pH, and the pKa of the model compound. The pharmacokinetic profile of caffeine in the suckling pup following iv bolus administration (5 mg/kg) was more prolonged compared with adult rabbits. The mean systemic clearance of total caffeine (CIs) in the adults and the pups was 3.83 +/- 1.94 and 1.14 +/- 0.80 ml/min/kg, respectively. The mean unbound systemic clearance (CIs,u) for caffeine was 5.09 +/- 2.60 ml/min/kg in the adults and 1.41 +/- 0.71 ml/min/kg in the pups.(ABSTRACT TRUNCATED AT 250 WORDS)