Food and Drug Administration regulation of medical device biotechnology, and food and food additive biotechnology.

The Food and Drug Administration (FDA) is facing a flurry of new products coming to market over the next few years that will be based on biotechnology. The agency will have to deal with state-of-the-art drugs and devices utilizing biotechnology as the developmental base. Also, many universities and companies are exploring the potential uses of biotechnology in developing new foods and food additives. This article will examine how the FDA is presently regulating medical device, and food and food additive biotechnology and the challenges confronting the agency in these areas in the future.

Urinary recovery of N-formimidoyl thienamycin (MK0787) as affected by coadministration of N-formimidoyl thienamycin dehydropeptidase inhibitors.

N-Formimidoyl thienamycin (MK0787) undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located on the brush border of the proximal tubular cells. The effects of two inhibitors (MK-789 and MK-791) of dehydropeptidase I on the pharmacokinetics of N-formimidoyl thienamycin were studied in 41 healthy subjects receiving various combinations of N-formimidoyl thienamycin and MK-789 or MK-791. Both inhibitors affected the plasma kinetics of N-formimidoyl thienamycin only to a small extent. Plasma concentrations and the area under the plasma concentration curve increased about 20% with a proportional decrease in plasma clearance. Plasma half-life was not altered significantly. Coadministration of MK-789 or MK-791 resulted in uniform and marked increases in urinary recovery and renal clearance of N-formimidoyl thienamycin. Thus, at an N-formimidoyl thienamycin/MK-791 ratio of 1:0.25 or higher, the urinary recovery was about 72% in all subjects, whereas it varied between 7.7 and 43% when N-formimidoyl thienamycin was given alone. The ratio of the N-formimidoyl thienamycin and MK-791 doses affected response. At relatively higher doses of MK-791, significant increases of N-formimidoyl thienamycin urinary recovery, renal clearance, and urine concentrations occurred during the later part of the 10-h observation period after each administration. At a 1:1 ratio of the two drugs, the inhibition of renal metabolism of N-formimidoyl thienamycin was maintained for at least 8 h, whereas renal clearance declined as soon as 4 h after the administration of a 1:0.25 ratio. The results indicated that MK-789 and MK-791 alter the renal excretion of N-formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular filtration only, possibly by competitively inhibiting the penetration of N-formimidoyl thienamycin into the proximal tubular cells.

MK0787 (N-formimidoyl thienamycin): evaluation of in vitro and in vivo activities.

The practical application of thienamycin, a novel beta-lactam antibiotic with a broad activity spectrum, was compromised by problems of instability. MK0787, N-formimidoyl thienamycin, does not have this liability. As reported, bacterial species resistant to most beta-lactam antibiotics, such as Pseudomonas aeurginosa, Serratis, Enterobacter, Enterococcus, and Bacteroides spp., are uniformly susceptible to MK0787, usually at one-half the inhibitory level of thienamycin. Bactericidal activity usually occurs at the minimal inhibitory concentration endpoint. Activity was reduced only at the highest inoculum densities tested and by a lessor factor than was observed with reference beta-lactam antibiotic active against P. aeruginosa and beta-lactamase-bearing strains. MK0787 exhibits a broad spectrum of in vivo activity when evaluated parenterally for efficacy against systemic infections in mice. The order of potency in vivo, 0.03 to 0.06 mg/kg for gram-positive species and 0.65 to 3.8 mg/kg for gram-negative infections including Pseudomonas, exceeded that of thienamycin and was at least 10-fold superior to reference beta-lactam antibiotics including two recently developed agents with antipseudomonal activity, cefotaxime and LY127935.

Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties.

A new beta-lactam antibiotic, named thienamycin, was discovered in culture broths of Streptomyces MA4297. The producing organism, subsequently determined to be a hitherto unrecognized species, is designated Streptomyces cattleya (NRRL 8057). The antibiotic was isolated by adsorption on Dowex 50, passage through Dowex 1, further chromatography on Dowex 50 and Bio-Gel P2, and final purification and desalting on XAD-2. Thienamycin is zwitterionic, has the elemental composition C11H16N2O4S (M.W. = 272.18) and possesses a distinctive UV absorption (lambda max = 297 nm, epsilon = 7,900). Its beta-lactam is unusually sensitive to hydrolysis above pH8 and to reaction with nucleophiles such as hydroxylamine, cysteine and, to a lesser degree, the primary amine of the antibiotic itself. The latter reaction results in accelerated inactivation at high antibiotic concentrations.