Prostatic Secretions and Drug Transport

Aumuller and Seitz (1990) have reviewed the secretory mechanism for the sex accessory tissues. Isaacs (1983) also reviewed the concepts related to the fluid and drug transport properties of the prostate and seminal vesicles and has compared the composition and volume of prostatic secretion under basal stimulation and under neurologic stimulation during ejaculation or pilocarpine stimulation. Isaacs calculated that under neurologic stimulation there is a 205-fold increase in the total potassium, chloride, and sodium output over the basal secretory rate, and he has shown that the prostate is capable of secreting five times its total content of sodium and chloride during this active secretion. These findings show the tremendous transport powers of this system. Smith and Hagopian (1981) have studied the transepithelial voltage changes during prostatic secretion in the dog and have concluded that although sodium may move passively through the plasma in the prostatic fluid during ejaculation the movements of potassium and chloride ions involve active transcellular transport. Isaacs and associates (1983) have shown that the androgen-induced secretions can be blocked in the presence of estrogen, although the growth properties and biologic properties of the androgen on the prostate are not markedly altered. This would suggest a direct effect of estrogen in blocking a major transport system in the prostate.

Only a few compounds, including ethanol, iodine, and a few antibiotics, are capable of entering the semen by simple diffusion (Reeves, 1982). Drugs entering prostatic secretions have been of interest because of the prevalence of prostatitis and the need for new modalities of chemotherapy. Earlier, Stamey and colleagues had made extensive studies of the ability of chemotherapeutic agents to concentrate in the prostatic fluid of humans and dogs (Hessl and Stamey, 1971; Stamey et al, 1973), and many other investigators have also contributed to this knowledge (Madsen et al, 1968, 1978; Madsen, 1976; Fowler et al, 1982). Few drugs reach concentrations in the prostatic secretion that approach or surpass their concentrations in blood, but some exceptions are the basic macrolides erythromycin and oleandomycin, sulfonamides, chloramphenicol, tetracycline, clindamycin, trimethoprim, and fluoroquinolones (Reeves, 1982).

In general these drugs are assumed to pass across the membrane by nonionic diffusion, possibly by lipid solubility, through the membrane; when they reach the more acidic prostatic fluid they are protonated and acquire a more positive charge. Thus the charged drugs become relatively trapped within the prostatic secretions. Several factors are critical, including the pKa of the drug and the pH of the prostatic secretions, as well as the drug binding to proteins in each compartment. Basic drugs would be more positively charged in acidic prostatic fluid than in blood. Slight changes in pH can have large effects on this nonionic diffusion. Samples of prostatic secretions from humans varied widely in pH from 6 to 8, with a mean value of 6.6; however, with prostatic inflammation the pH tended to be 7 or higher (White, 1975). Although prostatic secretions are slightly acidic, the pH of freshly ejaculated human semen is slightly alkaline (pH 7.3 to 7.7); on standing, semen first becomes more alkaline with the loss of carbon dioxide and then later acidic owing to accumulation of lactic acid. Drugs may be developed in the future that are transported into the prostate as therapeutic agents, as chemoprotectors, or as a route to the semen to regulate fertility; however, more must be learned about the fundamental transport system in and out of the male reproductive tract before such an approach is feasible.

Key Points: Prostatic Secretions and Drug Transport

• Only a few compounds, including ethanol, iodine, and a few antibiotics, are capable of entering the semen by simple diffusion.

• A few exceptions for drugs are the basic macrolides erythromycin and oleandomycin, sulfonamides, chloramphenicol, tetracycline, clindamycin, trimethoprim, and fluoroquinolones. Perhaps these molecules, because of their lipid solubility, are transported by nonionic diffusion.