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The purpose of the present review was to systematically evaluate if aqueous solubility, dose/solubility ratio, and partition coefficient (Log P ) could be used as useful parameters to quantitatively probe the dependence and correlation of in vivo food effects with these physicochemical properties of orally active drugs administered as immediate-release (IR) formulations. Mean AUC data obtained under fasted and fed states of over 100 structurally diverse orally active drugs with different physicochemical properties were obtained from the primary literature. Correlations of AUC ratio (Fed/Fasted) with aqueous solubility, dose/solubility ratio, and Log P were derived and statistically evaluated by Pearson's correlation test (two-tailed). A negative correlation was obtained between the logarithm of the aqueous solubility and the AUC ratio (r 5 À0.5982, N 5 93), whereas a positive correlation existed between AUC ratio and Log P (r 5 0.5147, N 5 110) and between AUC ratio and dose/solubility ratio (r 5 0.5511, N 5 87). All these correlations were significant (Po0.0001). Based on this study, the estimated range within which a drug is not expected to be significantly affected by food falls between 0.148-89.39 mg/ml for aqueous solubility and between 0.23-624 ml for the dose:solubility ratio. The corresponding range of Log P for expecting a lack of food-effect lies between À1.13 and 2.98. Quantitatively, the effect of food was most pronounced for lipophilic, poorly water-soluble drugs (with only a few exceptions), irrespective of whether the drug is acidic, basic, or neutral. It is concluded that aqueous solubility, dose/solubility ratio, and partition coefficient can be used as useful parameters to probe the dependence and correlation of food-effect with these physicochemical parameters for immediate-release formulations. Drug Dev. Res. 65:55-75, 2005.

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The Effects of Renal Impairment on the Pharmacokinetics of Zalcitabine

Bazunga

Tran

Kertland

et al. 1998

The Journal of Clinical Pharma

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The pharmacokinetics of zalcitabine (ddC) were studied in three groups of subjects with varying degrees of renal function: group I (n = 5), creatinine clearance (Clcr) 0-10 mL/min; group II (n = 10), Clcr 11-50 mL/min; and group III (n = 8), Clcr > 50 mL/min. Each patient received a single 0.75-mg oral dose of zalcitabine, and multiple blood and urine samples were collected over a 10-hour period after administration. Plasma and urine concentrations of zalcitabine were measured by high-performance liquid chromatography. No statistically significant differences were observed between the three groups in maximum concentration (Cmax), time to Cmax (tmax), or volume of distribution (V/F). Also, elimination half-life (t1/2), area under the concentration-time curve (AUC0-10), total body clearance (Cl/F), elimination rate constant (Ke), and renal clearance (Clr) did not differ significantly between the two groups with renal impairment (groups I and II). However, there was a significant difference in these parameters between groups with renal impairment (I and II) and group III. A linear correlation was observed between creatinine clearance (Clcr) and Clr, Ke, and Cl/F in all subjects. Clearance of zalcitabine is decreased after a single oral dose in patients with renal impairment. Dosage adjustment may be warranted in such patients, especially in those with severe renal impairment.

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Abstract: The results of this study show that the administration of zalcitabine with food results in a mild reduction in bioavailability. Although these changes are not expected to be of clinical importance, further studies must be conducted for confirmation.

Cited by 22 publications

References 8 publications

Effects of Food on Drug Absorption

Effects of Food on Drug Absorption

A quantitative approach to probe the dependence and correlation of food-effect with aqueous solubility, dose/solubility ratio, and partition coefficient (LogP) for orally active drugs administered as immediate-release formulations

The Effects of Renal Impairment on the Pharmacokinetics of Zalcitabine

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