Fluconazole: Interspecies Scaling and Allometric Relationships of Pharmacokinetic Properties

Abstract

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.

Prediction of human pharmacokinetics — renal metabolic and excretion clearance

“…The allometric exponents for these compounds -0.69 for creatinine and 0.67 for fluconazole -are close to that for GFR (~0.8;Campbell 1994). Jezequel (1994) found that about 80% of filtrated fluconazole was reabsorbed in the tubuli in seven species, including man. Fluconazole (polar surface area 78 Å 2 , f u,pl 0.88) is moderately lipophilic and has high intestinal P e and fraction absorbed (f a ) (0.95) (Zhao et al 2001;Willmann et al 2004).…”

“…In some cases, such as for creatinine and fluconazole, allometry has worked well for prediction of the excretion CL R in humans (Dedrick 1973;Jezequel 1994). The allometric exponents for these compounds -0.69 for creatinine and 0.67 for fluconazole -are close to that for GFR (~0.8;Campbell 1994).…”

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

“…Mahmood (1998) used allometry to predict human CL r for 10 compounds that were actively excreted from the kidneys, using data from at least three animal species, and found that the prediction errors ranged from 285% to +72% (Mahmood, 1998). However, it is interesting to note that allometry worked well for prediction of the CL r of creatinine and fluconazole, which involve tubular secretion in humans (Dedrick, 1973;Jezequel, 1994). It is likely allometric scaling works for compounds that have glomerular filtration as the main renal clearance mechanism, with minor active secretion and mainly passive reabsorption.…”

Pharmacokinetic-Pharmacodynamic Modeling of Alpha Interferon Response Induced by a Toll-Like 7 Receptor Agonist in Mice

“…2.1 liters/kg (21). Due to relatively similar tissue compositions in mice and rats, V tends to scale with an exponent close to 1 (19,27), and so the observed V at steady state (V ss ) in mice would appear to be high, given that the f u s in plasma for rats and mice are 0.22 and 0.33, respectively. However, bioavailability needs to be accounted for, and a low value of ca.…”