Fluconazole distribution

Fig. 9.1 Allometric relationship between body weight and volume of distribution of fluconazole.

Tab. 9.1 Comparison of absolute and weight normalised values for the volume of distribution of fluconazole in various species.

Absorption/Distribution - The pharmacokinetic properties of fluconazole are similar following administration by the IV or oral routes. In healthy volunteers, the bioavailability of oral fluconazole is more than 90% compared with IV administration. 

Like fluconazole, voriconazole (Muijsers et al., 2002) is polar, with moderate aqueous solubility (0.5 mg/mL), resulting in rapid absorption (maximum concentration achieved in less than 2 h) and oral bioavailability (96%). Moderate food effects have been observed. Distribution is wide with a steady-state volume of 4.6L/kg and moderate binding to plasma proteins (58%). 

Ketoconazole is well absorbed from the gut (poorly where there is gastric hypoacidity, see below) it is widely distributed in tissues but concentrations in CSF and urine are low its action is terminated by metabolism by cytochrome P450 3A (CYP 3A) (t) 8 h). Ketoconazole is effective by mouth for systemic mycoses (see Table 14.2) but has been superseded by fluconazole and itraconazole for many indications largely on groimds of improved pharmacokinetics, imwanted effect profile and efficacy. Impairment of steroid synthesis by ketoconazole has been put to other uses, e.g. inhibition of testosterone synthesis lessens bone pain in patients with advanced androgen-dependent prostatic cancer. 

In a group of children with fever, neutropenia, and neoplastic disease, there was an increase in renal fluconazole clearance (45). In infants and children, the volume of distribution of fluconazole is significantly higher and falls with age. With the exception of infants, who have a slower clearance rate, children clear the compound more rapidly (61). However, a second larger study reported slower elimination in children under 1 year of age, requiring dosage adjustments (62). Low birth-weight neonates have a particularly low clearance rate, which increases within weeks (63). 

Figure 35.8 Distribution of the drug fluconazole. Once taken in, compounds distribute themselves to various organs within the body. The distribution of the antifungal agent fluconazole has been monitored through the use of positron emission tomography (PET) scanning. These images were taken of a healthy human volunteer 90 minutes after...

ABSORPTION, DISTRIBUTION, AND EXCRETION Fluconazole is almost completely absorbed from the G1 tract irrespective of food or gastric acidity. Only 10% of drug in circulation is protein bound. Renal excretion accounts for >90% of elimination, with a of 25 hours. Fluconazole readily diffuses into body fluids, including breast milk, sputum, saliva, and CSF. The dosage interval should be increased from 24-48 hours for a creatinine clearance of 21 0 mL/min and to 72 hours at 10-20 mL/min. In renal failure, a dose of 100-200 mg is given after hemodialysis. 

Classification and pharmacokinetics The azoles used for systemic mycoses include ke-toconazole, fluconazole, itraconazole, and voriconazole. Oral bioavailability is variable (normal gastric acidity is required). Hueonazole and voriconazole are more reliably absorbed via the oral route than the other azoles. The drugs are distributed to most body tissues, but with the exception of fluconazole, drug levels achieved in the CNS are low. Liver metabolism is responsible for the elimination of ketoconazole, itraconazole, and voriconazole. Fluconazole is eliminated by the kidneys, largely in unchanged form. 

The volumes reflect binding to proteins and membranes. Only fluconazole, with its moderate lipophilicity and neutral character (low nonspecific binding), has a volume of distribution related to physiology (total body water). 

Fluconazole has good oral bioavarlabrlity irrespective of fed or fasted state, with greater than 90% of a dose bdng absorbed. Peak plasma levels are proportional to dose and are achieved within 1-2 hours of oral dosing. Plasma protein binding, half-life and the volume of distribution at steady-state are 10%, 25-30 hours and 0.55 L/kg,... 

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