AGE- AND GENDER-RELATED DIFFERENCES IN XENOBIOTIC TRANSPORTER EXPRESSION - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 590

20.7. Gender Differences in Transporter Expression
20.8. Mechanisms of Gender Differences
20.9. Conclusions
References
20.1. INTRODUCTION
For decades it has been known that infants cannot simply be regarded as miniature
adults when describing their response to drugs. However, the reasons for the differ-
ences between infants and adults have not been well delineated. Although variations
in pharmacokinetics and pharmacodynamics are assumed to be responsible for pro-
ducing these differences, their relative importance in producing these effects is not
understood. The purpose of this review is to illustrate the differences in expression of
drug transporters in young animals, as well as gender differences.
In laboratory animals the pharmacokinetics of numerous chemicals is different in
newborns than in adults. In general, chemicals are eliminated from the body more
slowly in young animals. In the 1960s it was determined that the expression of some
drug-metabolizing enzymes is not fully expressed at birth, which is responsible for
the delayed elimination of some xenobiotics from the body. 1 , 2
In the mid-1980s, when P-glycoprotein (multidrug resistance protein, Mdr) was
first cloned, 3 , 4 we began to understand the function of xenobiotic transporters in
eliminating xenobiotics from the body. Engineering of the first transporter-null mice in
the mid-1990s 5 enabled the scientific community to understand more thoroughly how
transporters affect the pharmacokinetics of xenobiotics. It is now generally accepted
that transporters play a critical role in the absorption, distribution, and elimination
of xenobiotics. It thus follows that variations in transporter expression can lead to
differences in pharmacokinetics, and therefore, differences observed in the age- and
gender-specific pharmacokinetics of drugs may be explained by differences in the
expression of xenobiotic transporters.
Mouse is the species in which the most thorough studies have been performed
to examine the gender- and age-related differences in transporters. Therefore, we
emphasize the data from mice, but data from other species are included where avail-
able. Whereas it would be desirable to quantify the transporter protein and function
at various ages, the availability of antibodies and specific substrates for the various
transporters are not available, and thus most of the data presented in this chapter relate
to mRNA.
20.2. HEPATOBILIARY TRANSPORTERS
20.2.1. Hepatobiliary Excretion in Newborns
Many but not all drugs and other foreign compounds are more toxic in newborn than
in adult animals, and some of these compounds, which are excreted primarily into