Health and Prostate

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Pharmacodynamics

The deficiency of 5-alpha-reductase was discovered more than 30 years ago. At this time, the role of 5-alpha-reductase inhibitors was hypothesized to be beneficial for the treatment of androgen-related diseases. Dihydrotestosterone (DHT) is the main prostatic androgen and is approximately twice as potent as testosterone; DHT binds to androgen receptors to induce androgenic effects in the prostate gland, liver, and skin. The enzyme 5-alpha-reductase is necessary to catalyze the conversion of testosterone to dihydrotestosterone. Five-alpha-reductase acts upon circulating testosterone, which when reduced to DHT accumulates in the prostate. There are two isoenzymes of 5-alpha-reductase: type 1 and type 2. The function of type 1 5-alpha-reductase is unknown. It has been found most commonly in sebaceous glands and is present in most body tissues. Type 2 5-alpha-reductase plays a role in prostate development and in the androgenic effects on the hair follicle. Finasteride inhibits mostly type 2 isoenzymes and is used for the treatment of benign prostatic hyperplasia (BPH) and alopecia. Approximately 85% to 90% of dihydrotestosterone is suppressed by the inhibition of type 2 isozymes. The remaining DHT is hypothesized to be from type 1 5-alpha-reductase. Dutasteride inhibits both type 1 and type 2 5-alpha-reductase and is also indicated for the treatment of benign prostatic hyperplasia.

Pharmacokinetics

The pharmacokinetic properties of finasteride and dutasteride are well-defined. The agents have good oral bioavailability and undergo extensive hepatic metabolism. Both agents are extensively metabolized via hepatic CYP 450 3A4 enzymes. Bioavailability is approximately 60% and is not affected by food. The half-life of both agents increases with age; however, no dosage adjustments are necessary. Biliary/fecal elimination appears to be similar, but finasteride undergoes approximately 39% renal elimination, whereas dutasteride data suggests virtually no renal elimination. Although plasma metabolites of finasteride will be higher in patients with renal impairment, the metabolites display less than 20% of the activity of the parent drug; therefore, no dosage adjustment is necessary. The effect of hepatic impairment on either agent is unknown at this time. Table 2 compares selected pharmacokinetic properties between finasteride and dutasteride.

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