Pharmacokinetics and tissue distribution of SB-251353, a novel human CXC chemokine, after intravenous administration to mice.

The pharmacokinetics and tissue distribution of SB-251353, a novel truncated form of the human CXC chemokine growth-related gene product beta, were studied after intravenous administration to the mouse (0.1--250 mg/kg). At the lowest dose, the clearance exceeded blood flow to the kidney. As the dose increased, clearance approached the glomerular filtration rate in the mouse. Clearance of this chemokine may be mediated by its pharmacologic receptor, CXCR2, via endocytosis with subsequent lysosomal degradation, as has been observed for several growth and hematopoietic factors. Apparent distribution volumes were high (> or =1 l/kg). Moderate binding to the Duffy antigen/receptor for chemokines on erythrocytes was observed. Consistent with the pharmacokinetic analysis, microscopic autoradiography showed uptake into renal proximal tubule epithelial cells. Limited excretion of SB-251353 in the urine (<2%) was consistent with catabolism of the chemokine in the tubules. Binding to hepatic sinusoids and connective tissue in the dermis was observed. This possibly reflected interaction of SB-251353 with heparin sulfate proteoglycan and may explain the large distribution volumes. This first study of the disposition of a chemokine provides insight into mechanism of action and physiological factors that may influence chemokine pharmacodynamics.

Disposition of metabolically radiolabeled CE9.1--a macaque-human chimeric anti-human CD4 monoclonal antibody--in transgenic mice bearing human CD4.

IDEC-CE9.1 is a macaque/human chimeric IgG1 monoclonal antibody (mAb) directed against the human T-lymphocyte receptor, CD4. CE9.1 is highly specific for the human receptor and is known to cross-react only with chimpanzee CD4. Thus, limited in vivo investigations have been performed that would be expected to reflect the behavior of this mAb in humans. CE9.1 was metabolically radiolabeled using [3H]leucine, and studies of the distribution and pharmacokinetics of [3H]CE9.1 were performed in transgenic mice bearing either the hCD4 receptor in place of the mouse receptor (CD4+), or no CD4 receptor (CD4-). Single-dose studies were performed after intravenous administration of approximately 0.4 and 100 mg/kg. The disposition of CE9.1 was highly dependent on the presence and distribution of the hCD4 receptor. After a low intravenous dose to CD4+ mice, rapid loss of [3H]CE9.1 from plasma (mean residence time < 1 hr) was accompanied by accumulation of radioactivity in the spleen (a maximum of 18% of the administered dose at 2 hr). By contrast, no significant uptake of radiolabel was observed in the spleen of CD4- mice after a low intravenous dose (< 1%), and plasma radioactivity exceeded 40% of the administered dose at 24 hr. Significant accumulation of radiolabel was observed in the liver of both CD4+ and CD4- mice (maximum of 9-13%), suggesting this process was not CD4-receptor-mediated. After a high intravenous dose to CD4+ mice, the mean residence time of CE9.1 was approximately 24 hr, and dose-normalized plasma area under the concentration vs. time curve was within a factor of 2 of that observed in CD4- mice. Spleen radioactivity was < 1% after a high intravenous dose to CD4+ mice, whereas in the liver, the profile of radioactivity was similar in CD4+ mice at 0.4 and 100 mg/kg.

Preclinical pharmacokinetic evaluation of the respiratory syncytial virus-specific reshaped human monoclonal antibody RSHZ19.

A preclinical evaluation of RSHZ19, a respiratory syncytial virus-specific reshaped human monoclonal antibody (IgG1 framework), has included pharmacokinetic studies in rats, adult cynomolgus macaques, and infant baboons after intravenous (iv), subcutaneous, or intramuscular (im) administration. After iv administration to rats and monkeys (1 mg/kg dose), a biphasic decline in plasma concentration was observed. The dominant terminal phase was characterized by an 11-day half-life in rats and a 21- to 24-day half-life in monkeys. Plasma clearances of 0.3 ml/hr/kg in the rat and 0.1-0.2 ml/hr/kg in the monkey were estimated. In the macaque, based on area under the curve, no evidence of significant nonlinearity in the pharmacokinetics was observed over a 200-fold dose range (1-200 mg/kg). In rat and monkey, absorption after extravascular administration was rapid relative to elimination (apparent half-lives < or = 24 hr), and bioavailability was high (> or = 82%). After iv or im administration to macaques (> or = 40 mg/kg), 1 of 3 animals in each group developed anti-RSHZ19 antibodies, and this resulted in rapid elimination of RSHZ19 from plasma. After the administration of a second im dose to macaques, no additional animals developed anti-RSHZ19 antibodies. Multiple-dose iv kinetics (5-day repeat dose) in infant baboons were modeled accurately by adult macaque data, suggesting that these species handled RSHZ19 similarly. The pharmacokinetic characteristics of RSHZ19 should support a convenient regimen for treatment or prophylaxis of human respiratory syncytial virus infection.

Renal catabolism of recombinant human soluble CD4 after intravenous administration to male Sprague-Dawley rats.

Recombinant soluble CD4 (sT4; mol. wt. 45,000) has been studied extensively in Sprague-Dawley rats, and substantial renal processing has been indicated. In rats and monkeys, renal filtration and precipitation of sT4 in the distal nephron caused tubular cast nephropathy. Intravenous pharmacokinetics in the rat demonstrated that sT4 plasma clearance exceeded the glomerular filtration rate. In an effort to determine quantitatively the extent to which kidney and other tissues were responsible for sT4 catabolism, sT4 was labeled with trace amounts of dilactitol-[125I]tyramine and administered intravenously to Sprague-Dawley rats (1 mg/kg). Dilactitol-tyramine accumulates in lysosomes at the site of protein degradation. It has been used primarily to demonstrate hepatic catabolism of endogenous proteins. Blood samples were drawn for pharmacokinetic analysis, and selected tissues were removed to assess radiolabel distribution. Comparison of pharmacokinetic parameters derived from total plasma radiolabel and functional ELISA were not significantly different. Thus, covalent modification of sT4 with dilactitol-tyramine did not appreciably change the rate of clearance. From 3 to 24 hr after intravenous administration, 81.5 +/- 0.1% of the total administered radioactivity was found in the kidney. Approximately 8-13% of the administered dose was recovered in the liver. Macroscopic autoradiography of the kidney demonstrated accumulation of radiolabel in the cortex. Light microscopic autoradiography of the kidney following intravenous administration of directly radioiodinated sT4 confirmed cortical processing, because radiolabel was located primarily in epithelial cells of P1 and P2 segments of the proximal tubule after low intravenous doses (0.4-4 mg/kg). At 40 mg/kg, distal tubules and cortical collecting ducts were labeled as well. Thus, sT4 was filtered by the glomerulus, reabsorbed in the proximal tubule, and degraded in the lysosomal compartment.

Disposition of growth hormone-releasing peptide (SK&F 110679) in rat and dog following intravenous or subcutaneous administration.

The disposition of growth hormone releasing peptide (SK&F 110679) has been studied in male Sprague-Dawley rats and in male and female beagle dogs following intravenous (iv) and subcutaneous (sc) administration. Mass balance/excretion of [3H]SK&F 110679 was assessed in bile duct-exteriorized rats from which radiolabeled biliary and urinary excreta were quantified and characterized. [3H]SK&F 110679 was excreted, predominantly in the bile, and to a large extent as intact peptide following either iv or sc administration. Although the extent of biliary excretion of radiolabel was similar following iv or sc administration (60-70% of the dose), the rate was significantly higher following iv administration. Using a specific plasma HPLC/fluorescence assay, the iv and sc pharmacokinetics of SK&F 110679 were investigated in both species. Following iv bolus administration, biphasic plasma concentration-time profiles were observed, and the initial phases were characterized by 2-4 min half-lives. Systemic plasma clearance was 27 ml/min/kg in the rat (0.4 mg/kg dose) and 17 ml/min/kg in the dog (0.5 mg/kg dose). High sc bioavailability (89-103%) was observed in both species; an apparent terminal half-life of 1 hr likely reflected slow absorption from the injection site.

Disposition of metabolically labeled recombinant soluble CD4 (sT4) in male Sprague-Dawley rats following intravenous and subcutaneous administration.

Soluble CD4 (sT4) has been metabolically labeled with [3H]leucine in Chinese hamster ovary cells and purified by S Sepharose chromatography. Over 250 microCi of high specific radioactivity [3H]sT4 (42 Ci/mmol) was prepared. The radiolabeled molecule was chemically and biologically representative of the unlabeled molecule and thus appropriate for in vivo metabolic investigations. To explore the biotransformation and disposition of a recombinant protein, this uniformly labeled [3H]sT4 was administered intravenously and subcutaneously to male Sprague-Dawley rats. Following a single dose of 0.3 mg/kg, blood samples were collected for 9 days and analyzed for total radioactivity, total plasma radioactivity, trichloroacetic acid-precipitable plasma radioactivity, sT4-related plasma radioactivity (by extraction with a Sepharose-bound polyclonal anti-sT4 antibody), and plasma sT4 concentration (by an N and C terminal-specific Leu3A/OKT4 ELISA). Excreta were analyzed for total radioactivity. The pharmacokinetic profiles of intact sT4 were as expected from the results of previous studies. sT4 was cleared rapidly from plasma with an elimination t1/2 of 7 min (intravenous), and low sT4 levels were observed following subcutaneous administration. Comparison of the kinetic profiles of total radiolabel, trichloroacetic acid-precipitable radiolabel, sT4-related radiolabel, and the isolation of plasma proteins containing tritium have led to the following conclusions. One of the major metabolic pathways for [3H]sT4 was the degradation of the polypeptide to its constituent amino acids, which were subsequently incorporated into endogenous proteins. Incorporation of tritium into blood cell proteins resulted in a prolonged radiolabel blood profile (t1/2 greater than 250 hr). Following subcutaneous administration, [3H] sT4 was significantly degraded before reaching the vascular circulation.