Fluconazole: interspecies scaling and allometric relationships of pharmacokinetic properties. 1994

S G Jezequel
Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, UK.

Fluconazole is a novel azole antifungal agent with low lipophilicity and high metabolic stability which has been investigated pharmacokinetically in six animal species and in man. The pharmacokinetic parameters of this drug have been compared across species and allometric relationships for fluconazole have been established. The volume of distribution was an 'invariant' parameter. When expressed in units corrected for bodyweight, the volume of distribution was constant across species, in keeping with being distributed throughout body water. Allometric relationships were obtained for total and renal clearance parameters. The closeness of the allometric exponents was in keeping with renal elimination accounting for most of the clearance in all species investigated. It also follows from the invariant characteristics of the volume of distribution term that an allometric relationship for plasma elimination half-life (t1/2) was also evident. Fluconazole thus possesses pharmacokinetic properties which are predictable for all terrestrial mammals. More detailed analysis of renal clearance (CLR) with regard to its relationship with glomerular filtration rate (GFR) has also been carried out. The data suggest that CLR is a direct function of GFR, involves only passive diffusion phenomena and that the extent of tubular re-absorption (approx. 80%) is constant across species. These observations are in keeping with the moderate lipophilicity and plasma protein binding of fluconazole and the incomplete re-absorption of the drug from the kidney tubules. It follows from these investigations that a knowledge of GFR in patients with altered renal function should allow a mechanistically based prediction of elimination characteristics of fluconazole.

UI MeSH Term Description Entries
D011817 Rabbits A burrowing plant-eating mammal with hind limbs that are longer than its fore limbs. It belongs to the family Leporidae of the order Lagomorpha, and in contrast to hares, possesses 22 instead of 24 pairs of chromosomes. Belgian Hare,New Zealand Rabbit,New Zealand Rabbits,New Zealand White Rabbit,Rabbit,Rabbit, Domestic,Chinchilla Rabbits,NZW Rabbits,New Zealand White Rabbits,Oryctolagus cuniculus,Chinchilla Rabbit,Domestic Rabbit,Domestic Rabbits,Hare, Belgian,NZW Rabbit,Rabbit, Chinchilla,Rabbit, NZW,Rabbit, New Zealand,Rabbits, Chinchilla,Rabbits, Domestic,Rabbits, NZW,Rabbits, New Zealand,Zealand Rabbit, New,Zealand Rabbits, New,cuniculus, Oryctolagus
D001835 Body Weight The mass or quantity of heaviness of an individual. It is expressed by units of pounds or kilograms. Body Weights,Weight, Body,Weights, Body
D002627 Chemistry, Physical The study of CHEMICAL PHENOMENA and processes in terms of the underlying PHYSICAL PHENOMENA and processes. Physical Chemistry,Chemistries, Physical,Physical Chemistries
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D006207 Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Halflife,Half Life,Half-Lifes,Halflifes
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001682 Biological Availability The extent to which the active ingredient of a drug dosage form becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action. Availability Equivalency,Bioavailability,Physiologic Availability,Availability, Biologic,Availability, Biological,Availability, Physiologic,Biologic Availability,Availabilities, Biologic,Availabilities, Biological,Availabilities, Physiologic,Availability Equivalencies,Bioavailabilities,Biologic Availabilities,Biological Availabilities,Equivalencies, Availability,Equivalency, Availability,Physiologic Availabilities
D012995 Solubility The ability of a substance to be dissolved, i.e. to form a solution with another substance. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed) Solubilities
D013045 Species Specificity The restriction of a characteristic behavior, anatomical structure or physical system, such as immune response; metabolic response, or gene or gene variant to the members of one species. It refers to that property which differentiates one species from another but it is also used for phylogenetic levels higher or lower than the species. Species Specificities,Specificities, Species,Specificity, Species

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