Decreased enzyme levels

and enzyme activity, and is due primarily to a down-regulation of CYP gene transcription, but modulation of RNA and enzyme inhibition may also be involved (58, 59).

As shown in Table 32.14, the expression of CYP2C11 and CYP2D isoenzymes is frequently suppressed by cytokines. These two CYP gene families are consti-tutively expressed in male and female rats. In the rat, CYP2C is under developmental and pituitary hormone regulation. Although there is approximately 70% cDNA-deduced amino acid sequence homol-ogy with the human CYP2C, caution is needed in extrapolating these observations on CYP2C regulation in rats to humans (59). In both rats and humans, there is polymorphic expression of the CYP2D and CYP2D1 isoenzymes, which exhibit debrisoquine 4-hydroxylase activity. However, this gene family has evolved differently in rats than in humans. Specifically, the rat has four genes that are approximately 73-80% similar while the human has three genes that are 89-95% similar. Thus, results in rat studies may not be predictive of results in humans because of the difference in number of genes, their regulation, and their complexity (60).

In vitro study results have been consistent with those obtained in vivo. For example, in primary rat hepatocyte cultures, IL-1, tumor necrosis factor (TNF), and interleukin-6 (IL-6) concentrations ranging from 0.5 to 10.0 ng/mL suppressed the expression of CYP2C11 mRNA (59). It is interesting to note that in rat liver microsomes, IL-2 increased both the amount of immunoreactive CYP2D protein and its mRNA (61). In human primary hepatocytes, IL-1b, Il-6, and TNF-a caused a decrease in all mRNAs and CYP isoenzyme activities. Moreover, interferon g (IFNg) was shown to decrease CYP1D2 and CYP2E1 mRNA, but had no effect on CYP2C or CYP3A mRNAs (57).

The clinical significance of the aforementioned findings is unknown. A report by Khakoo et al. (62) did not demonstrate a pharmacokinetic interaction between IFNa2fc and ribavirin or an additive effect of the combination therapy on safety assessments. In another study, administration of IFNa prior to the administration of cyclophosphamide significantly impaired the metabolism of cyclophosphamide and 4 hydrox-ycyclophosphamide. In contrast, the administration of IFNa after cyclophosphamide resulted in higher 4-hydroxycyclophosphamide concentrations and produced a significant decrease in leukocyte count (63).

Finally, the interaction between IL-2 and dox-orubicin was explored in patients with advanced solid tumors (64). Doxorubicin was given alone, and then 3 weeks later patients received the combination of rhIL-2 (18 mIU/m2 given SC on days 1-5)

and doxorubicin. Doxorubicin pharmacokinetics were assessed for 48 hours after each administration period. SC injections of rhIL-2 did not affect doxorubicin PK. Doxorubicin, given before IL-2, prevented IL-2-induced lymphocyte rebounds but not did not qualitatively alter nonmajor histocompatibility complex-restricted cytotoxicity. Thus, various cytokines have been shown to affect CYP protein content, mRNA, and enzyme activities. However, there are few reports that evaluate the extent and clinical significance of corresponding PK or PD changes.

Little is known regarding the catabolism of proteins that are either currently marketed or under investigation. The absence of suitable biological assays or other analytical methods for identifying and quanti-tating protein degradation products obviously limits evaluation of this catabolism. Similarly, the catabolism of mABs (in particular, the catabolism of the Ig molecule) is complex and not well understood (65). mAB catabolism reflects the basal metabolic rate of the body as well as the function of phagocytic cells [monocytes, macrophages of the reticuloendothelial system (RES)]. There is also a relationship between IgG concentration and catabolism that is specific for each IgG molecule — the higher the IgG concentration, the shorter the survival time. To explain this characteristic of immunoglobulins, Brambell et al. (66) hypothesized, and Junghans and Anderson (67) have confirmed, that there is a specific, saturable receptor for each immunoglobulin that, when bound, protects the IgG from degradation. The IgG subclasses differ from one another in their amino acid sequence and Fc fragment, with survival half-lives of approximately 20 days for IgG1, IgG2, and IgG4, but 7 days for IgG3(7). The location and mechanism of IgG metabolism is not known but is believed to involve uptake by pinocytic vacuoles, release of proteolytic enzymes, and subsequent degradation of unbound IgG.

Renal Excretion

The renal excretion of proteins is size dependent and glomerular filtration is rate limiting. It has been suggested that the renal clearance rate of macromolecules, relative to the glomerular filtration rate of inulin, decreases with increasing molecular radius (68). The following general conclusions are based on studies using indirect methods to estimate the glomerular sieving coefficients. Small proteins (<25 kDa) cross the glomerular barrier, and filtration accounts for most of their plasma clearance; the degree of sieving is independent of biologic activity and the filtered load of protein is directly related to plasma concentration. The effect of molecular charge

TABLE 32.15 Cell Surface Receptors for the Clearance of Carbohydrates and Monosaccharides


Cell type


Liver parenchymal cells (asialoglycoprotein

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