Fluconazole: interspecies scaling and allometric relationships of pharmacokinetic properties.
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.
Jezequel
S G
SG
Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, UK.
D000818:Animals; D001682:Biological Availability; D001835:Body Weight; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D015725:Fluconazole / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D051379:Mice; D011817:Rabbits; D051381:Rats; D012995:Solubility; D013045:Species Specificity
D015725:Fluconazole