No abstract

Pharmacokinetics may be defined as what the body does to a drug. It deals with the absorption, distribution, and elimination of drugs but also has utility in evaluating the time course of environmental (exogenous) toxicologic agents as well as endogenous compounds. An understanding of 4 fundamental pharmacokinetic parameters will give the toxicologic pathologist a strong basis from which to appreciate how pharmacokinetics may be useful. These parameters are clearance, volume of distribution, half-life, and bioavailability.

SUMMARYThe type 2 helper T cell (T H 2) cytokine interleukin (IL)-4 is thought to play a central role in the early stages of asthma. In an effort to develop an antibody treatment for asthma that neutralizes the effects of IL-4, a murine monoclonal antibody, 3B9, was generated with specificity for human IL-4. In vitro studies demonstrated that 3B9 inhibited IL-4-dependent events including IL-5 synthesis, T H 2 cell activation and up-regulation of immunoglobulin E expression. 3B9 was then humanized (pascolizumab, SB 240683) to reduce immunogenicity in humans. SB 240683 demonstrated species specificity for both monkey and human IL-4 with no reactivity to mouse, rat, cow, goat or horse IL-4. Pascolizumab inhibited the response of human and monkey T cells to monkey IL-4 and effectively neutralized IL-4 bioactivity when tested against several IL-4-responsive human cell lines. Affinity studies demonstrated rapid IL-4 binding by pascolizumab with a slow dissociation rate. In vivo pharmacokinetic and chronic safety testing in cynomolgus monkeys demonstrated that pascolizumab was well tolerated, and no adverse clinical responses occurred after up to 9 months of treatment. Three monkeys developed an anti-idiotypic response that resulted in rapid pascolizumab clearance. However, in the chronic dosing study the antibody response was transient and not associated with clinical events. In conclusion, pascolizumab is a humanized anti-IL-4 monoclonal antibody that can inhibit upstream and downstream events associated with asthma, including T H 2 cell activation and immunoglobulin E production. Clinical trials are under way to test the clinical efficacy of pascolizumab for asthma.

The stability of naproxen glucuronide (NAP-G) diastereomers was investigated in buffer, 0.3% and 3% human serum albumin (HSA) solutions, and human plasma. R-NAP-G was found to be less stable in phosphate buffer than its S-diastereomer, whereas incubation media containing protein in general increased the degradation rate of NAP-G but also caused a change of the stereoselective stability where the R-NAP-G was more stable than S-NAP-G. Reversible binding of NAP-Gs to HSA (0.3%) was investigated and compared with the corresponding properties of naproxen (NAP) enantiomers. NAP-G diastereomers exhibited a considerable and stereoselective affinity to HSA, although less than that observed for the NAP enantiomers. In vitro irreversible binding of NAP-Gs to HSA, human and rat plasma proteins was also investigated. Irreversible binding was higher for R-NAP-G (50 microM) than for S-NAP-G (50 microM) in all incubation media. This stereoselective difference was observed with HSA containing medium as well as in rat and human plasma. Incubation with unconjugated NAP did not lead to irreversible binding. Preincubation of HSA with acetylsalicylic acid (approximately 11 mM) and glucuronic acid (50 mM) decreased the extent of irreversible binding suggesting involvement of lysine residues for covalent binding. Preincubation with S-NAP also decreased the irreversible binding yield.