Jerome A. Moore

Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins

The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immuno-globulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the pre-clinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.

Absorption of recombinant methionyl-human growth hormone (Met-hGH) from rat nasal mucosa

Abstract The absorption of recombinant methionyl human growth hormone (Met-hGH) from the nasal mucosa into the systemic circulation was studied in anesthetized rats. Met-hGH was administered intranasally (i.n.), intramuscularly (i.m.) and intravenously (i.v.) to determine the relative and absolute bioavailability of an intranasal Met-hGH formulation. In the absence of detergent enhancers, the absolute bioavailability of meth hGH was

Absorption enhancement of growth hormone from the gastrointestinal tract of rats

Abstract An increased interest in non-injectable dosage forms for polypeptides has led to identification of some compounds which can increase absorption of these drugs. Sodium salicylate administered in rectal suppositories with recombinant methionyl human growth hormone (met-hGH) lead to measurable serum concentrations and demonstratable biological activity of the polypeptide. Sodium salicylate and mineral oil were tested in the ligated stomach, duodenum, ileum and colon of rats for their ability to enhance absorption of met-hGH. Rats were injected in one of the segments of the gastrointestinal tract with 3 mg kg of met-hGH with or without sodium salicylate in aqueous buffer or mineral oil vehicle. Blood samples were collected at various time points and assayed for hGH. Absolute bioavailabilities calculated for each formulation in each intestinal segment indicated that the only treatment with greater than 3% bioavailability was injection of sodium salicylate in mineral oil into the ileum (7%) and colon (9.5%). Statistical analysis proved the surprising interaction of salicylate and mineral oil to be synergistic in absorption enhancement. This is a promising finding but several issues must be addressed and pharmaceutical formulations must be optimized before it can be developed into an oral dosage form for polypeptide drugs.

Pharmacokinetics and Metabolism of Protein Hormones

The therapeutic potential of biosynthetic protein hormones is often determined by the half-life of the administered protein in the circulation. Most of the proteins tested display rapid serum clearance following intravenous administration relative to more conventional therapeutics. Tissue localization studies with radiolabeled hormones indicate that the liver and kidney are the primary organs of elimination for exogenously administered proteins. This observation, as will be discussed below, must be cautiously interpreted, however, as it is often subject to experimental artifact. The pharmacokinetic profiles of exogenously administered protein hormones are influenced by interactions with specific binding proteins and clearance by receptor- and non-receptor-mediated uptake and degradation (Maack et al., 1979; Posner et al., 1982; Walton et al., 1989; Baumann et al., 1990). Peripheral metabolism of protein hormones involves, predominantly, the hydrolysis of the amino acid backbone by a combination of exo- and endoproteinases (Bond and Butler, 1987). Proteolysis is involved in terminating the action of the molecule and may be related to the pharmacology of the hormone by producing molecules having biological activity. These differences may be related to processing at target versus nontarget tissues. Therefore, determining peripheral sites of degradation and the cellular mechanisms involved in regulating the catabolism or processing of an administered protein may contribute to the design of molecules possessing desirable kinetic or pharmacological properties.

PHARMACOLOGICAL COMPARISON OF TWO HYBRID RECOMBINANT DNA-DERIVED HUMAN LEUKOCYTE INTERFERONS

ABSTRACT. Two hybrid human leukocyte interferons differing in only three amino acid residues show marked differences in various pharmacological properties. One hybrid, IFN-αAD (Bgl) shows greater antiviral activity in vitro and in vivo and suppresses P-450 metabolism of drugs including hexobarbital and acetaminophen. The pharmacokinetics of this hybrid and IFN-αAD (Pvu) are also distinct.

Delivery Systems for Recombinant Methionyl Human Growth

The advent of recombinant DNA technology has lead to an increased interest in convenient, effective pharmaceutical dosage forms for polypeptide drugs. It is well known that there are many obstacles to delivery of these compounds by conventional dosage forms. Large molecular weight, solubility problems, suseptibility to enzymatic degradation, sensitivity to pH and temperature, and short in vivo half life are some of the problems that must be confronted. For drugs with such complex biological activities as most therapeutic polypeptides one of the biggest obstacles to development of delivery systems is lack of information on the mechanism of action of the drug.