Role of the red blood cell in drug metabolism

The major function of the red blood cell (RBC) is to exchange oxygen for carbon dioxide at the tissue level. To perform this role the RBC is equipped with numerous enzyme systems whose functions it is to maintain the energy supply of the cell and to protect its main components, haemoglobin and the cellular membrane, from oxidation by a range of electrophiles. In contrast to other cells, the mature RBC has no mitochondria, is not nucleated, has no ribosomes or m-RNA and so is incapable of protein synthesis. It does not possess a functional urea cycle. It is partly for these reasons that the RBC is considered to have limited metabolic capacity. This is assumed to mean that the RBC is not actively engaged in drug metabolism since this process has become synonymous with cytochrome P-450 and conjugation, neither of which are considered to be present in the blood, or more particularly in RBC. Pharmaceutical scientists have assumed blood to be an inert vehicle for the transportation of drugs to target tissues, and a pool from which to sample in order to extrapolate to the concentration of drug at the target tissue. Implicit in that assumption is that the blood itself is not a site of metabolism of the agent under investigation. Much evidence has, however, accumulated to suggest that the blood, and RBC in particular, is far from being inactive in drug metabolism. The purpose of this review is to inform the reader of the numerous enzymes or enzyme-like activities present in the RBC which have been shown to participate in drug metabolism, at least in vitro (Table I). Whether these reactions play an important role in in vivo drug metabolism or whether they only have importance in producing in v i m artefacts to confound proper pharmacokinetic analysis will be discussed.