Lactational State Modifies Alcohol Pharmacokinetics in Women

A wide variety of drugs, including alcohol (da-Silva et al., 1993; Kesaniemi, 1974; Lawton, 1985; Mennella and Beauchamp, 1991), enter breastmilk and affect the lactational processes of milk production and the behavior and physiology of the recipient infant (Dorman et al., 2001; Hale et al., 2004; Little et al., 1989; Mennella and Beauchamp, 1991; Mennella et al., 2005). Much less is known about how the dynamic physiological processes that occur during lactation influence the absorption, distribution, and elimination of drugs and how such changes in drug pharmacokinetics impact the health of lactating women (Dan et al., 1993; Mitani et al., 1987; Nahum et al., 2006). Several lines of evidence from human and animal models support the hypothesis that lactational state could alter drug pharmacokinetics. First, the growth of the mammary glands during lactation provides a new compartment of drug distribution, excretion (Clewell and Gearhart, 2002), and possibly metabolism as alcohol dehydrogenase (ADH) is expressed in breast tissue (Saleem et al., 1984; Triano et al., 2003). Second, the high nutritional demands associated with milk production coincide with remarkable changes in the gastrointestinal tract (Hammond, 1997; Hunt and Murray, 1958; Uvnas-Moberg et al., 1987). In rodents, lactation is associated with dramatic intestinal growth (e.g., increased height of the villi) and a generalized hypertrophy and hyperplasia of the mucosal epithelium (Hammond, 1997). Such lactation-induced changes in the gastrointestinal tract significantly extend the surface area of the intestines, which, in turn, may modulate nutrient as well as drug absorption. Third, the act of nursing results in a surge of hormones (e.g., oxytocin) and gastrointestinal regulatory peptides that modifies the rate of gastric emptying (Franceschini et al., 1990; Holst et al., 1986; Ohlsson et al., 2004; Uvnas-Moberg et al., 1987; Widstrom et al., 1984; Winberg, 2005) and, in turn, may modify the pharmacokinetics of a variety of orally administered drugs including alcohol (Oneta et al., 1998; Pang, 2003). Fourth, the hypertrophy of the liver (da-Silva et al., 1996; DeSantiago et al., 1998; Gordon et al., 1985), and altered liver enzyme levels and liver functioning during lactation (David et al., 2000; Tigas et al., 2002) may affect the liver’s oxidative capacity and, in turn, alter drug metabolism. For example, it has been suggested that the lactation-induced liver hypertrophy contributes to the significantly faster rate at which alcohol is eliminated in lactating when compared with nonlactating rats (Abel et al., 1979; Gordon et al., 1985). Similarly, reproductive state may alter the activity of enzymes (e.g., ADH, microsomal ethanol oxidizing system) responsible for the metabolism of alcohol in the liver as well as other sites (Badger et al., 2005; Gordon et al., 1985). Information on alcohol pharmacokinetics during lactation in humans is limited to one study of 5 lactating women and 8 nonlactating control women. Three of the women in the control group were tested within months of stopping breastfeeding and the parity of the other 5 was not reported. Nevertheless, the data revealed that blood alcohol levels peaked later and the mean area under the blood alcohol time curve (AUC), an indicator of systemic availability of the drug, was significantly smaller in lactating women (da-Silva et al., 1993). However, unlike that observed in rodents (Abel et al., 1979), there were no significant differences in alcohol elimination rates. The lack of differences in alcohol disappearance rates may be due to the lack of appropriate control groups or statistical power because of the limited sample size or both. Therefore, the hypothesis that alcohol is eliminated at a faster rate during lactation cannot be rejected. Given the physiological adaptations of the digestive system during lactation (Hammond, 1997; Hunt and Murray, 1958; Uvnas-Moberg et al., 1987), the present study tested the hypotheses that lactation alters alcohol pharmacokinetics and that the metabolic differences between lactating and nonlactating women would be more striking when analyzing alcohol pharmacokinetics when alcohol was consumed with a meal. To this end, we studied lactating women who were exclusively breast feeding a 2- to 5-month-old infant and 2 control groups of nonlactating women under 2 conditions: when alcohol was consumed following a meal or on an empty stomach. The first control group consisted of women who were exclusively formula-feeding similarly aged infants, whereas the other consisted of women who had never given birth. These 2 control groups were included to determine whether differences, if any, observed between the groups were due to lactation per se and not a consequence of the physiological changes that occur during pregnancy and parturition. Subjective ratings of mood and drug effects during the rising and falling portions of the blood alcohol concentration (BAC) time curve were also obtained to determine whether reproductive state was associated with changes in the biphasic effects of alcohol.