Male Genital Tract Pharmacology: Developments in Quantitative Methods to Better Understand a Complex Peripheral Compartment

Abstract

A substantial health burden results from medical problems affecting the male genital tract, including chronic morbidity conditions affecting a large proportion of men, such as benign prostatic hypertrophy and prostatitis, and potentially lethal conditions, such as prostate cancer and human immunodeficiency virus transmission. Rational approaches to therapeutics in these conditions should benefit from understanding local pharmacokinetics and pharmacodynamics of active drugs within the male genital tract. However, the description of drug distribution into the male genital tract has been largely limited to total, rather than protein-free drug concentrations in the whole ejaculate at one or two time points within a dosing interval, which may be misleading in understanding local drug action. Recent innovations enable a quantitative understanding of protein-free drug kinetics into semen and drug distribution into individual male genital tract glands. These methods may benefit therapeutics through optimization of targeted drug delivery and facilitate drug development for diseases related to these glands.

Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

“…However, split ejaculation sampling is challenging and has not yet yielded data suggesting differential penetration of antiretrovirals that are of clinical consequence [97]. As such, composite semen samples have typically been used as a relatively practical surrogate marker for MGT drug exposure [98]. …”

“…Earlier discussions regarding protein binding in CVF also apply to semen. Semen contains a considerably smaller concentration of albumin relative to blood plasma (approximately 1 g/L vs. 40 g/L) [98]. This difference may lead to reduced protein binding within SP and result in higher concentrations of active free drug.…”

High Concentration of Raltegravir in Semen of HIV-Infected Men: Results from a Substudy of the EASIER-ANRS 138 Trial

“…Indeed, drug diffusion into semen depends on a number of factors, such as lipid solubility, ionization, plasma protein binding, and substrate of uptake or efflux transporters (1,20). Raltegravir is expected to be mostly ionized in plasma, but ionization in the whole ejaculate is predicted to be negligible on the basis of pH-pK a partitioning, as previously described for other antiretroviral drugs (1).…”

“…However, slight lipophilicity and pharmacokinetic properties (83% bound to plasma proteins) could support passive diffusion from blood to semen. Raltegravir was demonstrated to be a substrate of the efflux transporter MDR1 (2); however, limited information is available on the presence of this transporter within the male genital tract (1,20).…”

A highly sensitive ultra performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) technique for quantitation of protein free and bound efavirenz (EFV) in human seminal and blood plasma

“…Many ARV drugs, however, inadequately penetrate into the male genital tract (MGT). Limited drug access to the MGT would permit viral replication and could potentially engender resistance, creating a “pharmacological sanctuary.” The mechanism of ARV drug penetration and distribution into the MGT is largely unknown [2]. Many ARV's have large blood plasma: seminal plasma ratios of total drug concentrations [3].…”