Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Distribution in Tissue

Tissue Penetration of Antifungal Agents

“…1) and may explain persistent antifungal activity when plasma concentrations are low or undetectable (e.g., as seen with L-AMB [30], caspofungin [31], and itraconazole [76]). Conversely, suboptimal target site concentrations may well explain some cases of therapeutic failure (11,13). In addition, as most fungal infections are extracellular, interstitial fluid may be the closest measurable compartment to the site of infection.…”

“…(ii) physiological factors, such as inflammation, which may increase tissue permeability, i.e., by disruption of normal physiological barriers such as the blood-brain barrier (29,40); the underlying disease (41), which may result in a range of effects, including modification of plasma protein composition and hence drug binding (42,43,44); the recruitment of drug-containing phagocytic cells, i.e., the "dump truck phenomenon," which may increase drug concentrations at the site of infection (12,13,32,45,46); drug export via pumps, e.g., for itraconazole and P-glycopro- Fluid multiples are from g/ml concentrations. *, autopsy data; in these cases, the multiples are based on plasma C max values at the same dose in volunteers (188).…”

“…For example, the lipophilicities (expressed as log D values in Table 1) of the four triazoles vary from 0.5 to Ͼ5.0, and plasma protein binding ranges from 12% to Ͼ99% (Table 1). These physicochemical properties determine the rate and extent of tissue penetration and bioavailability within a tissue, organ, or fluid (13,34). Tissue and fluid concentrations for the three triazoles (fluconazole, voriconazole, and itraconazole), as multiples of those in blood or plasma, are shown in Fig.…”

“…Penetration into the site of infection to achieve microbe-eliminating concentrations is a key requirement for efficacy of all antimicrobial agents (11,12,13,14,15). The importance of tissue concentrations for the various classes of antibacterial agents has been reviewed extensively, but relatively less attention has been paid to the currently available antifungal agents (12,16,17,18,19).…”

Enantiomeric radiochemical synthesis of R and S (1‐(6‐amino‐9H‐purin‐9‐yl)‐3‐fluoropropan‐2‐yloxy)methylphosphonic acid (FPMPA)

“…However, the blood comprises only 2% of total target cells in the body. Tissue drug levels may substantially differ from corresponding plasma levels, and drug distribution processes may be characterized by high intertissue variability, leading to suboptimal target site concentrations and the potential risk for therapeutic failures 5 . Biopsies, for certain lymphoid organs, have frequently been applied to measure drug concentrations in tissues.…”