Drug Interactions in the Treatment of ED, LUTS and BPH: 5-Alpha-Reductase Inhibitors

Posted by admin on December 24th, 2009 No Comments

Contents

Pharmacodynamics
Pharmacokinetics

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.

Table 2. Pharmacokinetic Parameters of 5-Alpha-Reductase Inhibitors
Agent/ Formulation	Bioavailability	Protein Binding	Half-Life	Metabolites	Elimination
Finasteride Film-coated tablets	63%	~ 90%	6 15 h	Two metabolites with < 20% activity	Biliary (57%) Renal (39%)
Dutasteride Soft gelatin capsules	59%	> 99.5%	5 weeks	6-beta- hydroxydutasteride (active)	Fecal (~ 45%) Renal (~ 1%)

5-Alpha-Reductase Inhibitors Overview The basis for using 5-alpha-reductase inhibitors (5-ARIs) to treat benign prostatic hyperplasia stems from the observation that men with congenital 5-alpha-reductase deficiency have abnormally small prostates. Because 5-ARIs reduce prostate size, they are useful in treating patients with enlarged prostates — the subset ...
5-Alpha-Reductase Inhibitors Overview Because inhibition of the enzyme 5-alpha-reductase is known to reduce prostate size, patients with an enlarged prostate (greater than 40 g) are often prescribed a 5-alpha-reductase inhibitor (5-ARI). Along with alpha Mockers, 5-ARIs dominate the benign prostatic hyperplasia drug market. The agents currently ...
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Drug Interactions in the Treatment of ED, LUTS and BPH: Selective Alpha-1-Adrenergic Receptor Blockers Pharmacodynamics Alpha1 receptors are located in nonvascular smooth muscles (e.g., bladder trigone and sphincters, gastrointestinal tract and sphincters, prostate adenoma and capsule, and ureters) and in nonmuscular tissues (e.g., central nervous system, liver, and kidneys). Symptoms of benign prostatic hyperplasia (BPH) are related to bladder ...
Drug Interactions in the Treatment of ED, LUTS and BPH: Clinically Relevant Drug-Drug Interactions Clinically Relevant Drug-Drug Interactions With the 5-Alpha-Reductase Inhibitors Neither dutasteride nor finasteride have any clinically significant pharmacodynamic or pharmacokinetic adverse drug interactions. Studies show that the 5-alpha-reductase inhibitors do not affect the CYP 450 enzyme system. However, agents that inhibit the CYP 450 3A4 may, ...

Tags: Dutasteride, Finasteride
Posted in: Benign Prostatic Hyperplasia

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