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Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a racemate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case-by-case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.

When evaluated at 15 C, insulin binding to human erythrocytes is similar to that of human adipocytes fibroblasts, monocytes and placental membranes. At 37 C, however, both insulin binding and degradation by human erythrocytes have a unique character. At this temperature, by the end of the first 30 minutes, erythrocyte specific insulin binding is 3 to 4% of the total available insulin. This percentage of binding remains until the end of the first hour, then for the next four hours, increases linearly to 24%. Intact erythrocytes had negligible degradation of the free 125I-insulin but 56% of the 125I-insulin associated with the erythrocytes was degraded after five hours of incubation at 37 C. The degradation of the bound insulin was determined to be an intracellular property of erythrocytes. This degradation may be the mass action driving force responsible for the increased association of 125I-insulin observed after one hour of incubation. On the other hand, erythrocyte ghosts reached a steady state with 2% of the 125I-insulin bound after 1.5 hours of incubation at 37 C. More than 94% of the bound and free insulins were intact after 5 hours of incubation. These observations indicate, for the first time, that erythrocyte insulin degrading activity is localized inside the cells, not in their membranes, and that the human erythrocyte with its insulin receptors may be one of the important cell types in the metabolism of insulin.

Chronic renal failure is associated with altered insulin sensitivity of unclear etiology. To investigate the effect of renal failure on insulin binding, we studied insulin binding in mature erythrocytes from 5 undialyzed and 12 chronically dialyzed patients with renal failure. The cell suspension of the isolated and purified human erythrocytes (3.52 × 10⁹/ml) was incubated with 100 pg of ¹²⁵I-insulin and a range of unlabeled insulin concentrations (pH 8.0, 15°C for 3.5 h). A maximum of 7.9 ± 1.6 and 14.1 ± 3.5 (mean ± SD) specific percent of ¹²⁵I-insulin was bound by the undialyzed and dialyzed patients respectively, as compared to 10.1 ± 1.4 (mean ± SD) maximum specific percent of insulin bound by the normal subjects. Scatchard plots from the normal, undialyzed and dialyzed subjects were curvilinear, indicating negatively cooperative insulin receptor site-site interactions. From the DeMeyts1 analyses of the Scatchard plots, it was determined that the unoccupied receptor site affinity constant, K_e, for the normal subjects was 0.5 × 108 M^-1 whereas that for the undialyzed and the dialyzed patients was 0.69 × 108 M^-1. The normal subjects had 410 receptor sites per erythrocyte; however, the undialyzed patients had 215 sites per cell and the dialyzed patients had a receptor number similar to that of the normal subjects. The undialyzed patients had 48% fewer receptor sites than the dialyzed patients and the normal subjects. The undialyzed patients comparing with the normal subjects thus, showed a reduction in insulin binding and in the number of receptor sites with increased affinity. Chronic dialysis caused an increase of insulin binding and of receptor number when compared with the undialyzed patients. In the undialyzed patients with renal failure, the defect in receptor number may be associated with a defect in tissue response to insulin. This defect in insulin receptor number was removed with chronic dialysis. Thus, chronic dialysis may improve insulin sensitivity at the cellular level.

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