Norethisterone (Primolut Nor) Elimination
Norethisterone is primarily eliminated through hepatic metabolism followed by renal excretion of metabolites, with minimal unchanged drug excreted in urine.
Primary Elimination Pathway
Norethisterone undergoes extensive hepatic biotransformation before excretion, contrasting sharply with drugs like amantadine that are excreted 90% unchanged in urine 1, 2.
The drug is metabolized through multiple pathways including 5α-reduction and hydroxylation to form various metabolites including 5β-NET, 5α-NET, and tetrahydro-NET derivatives 3, 4.
At least six major metabolites have been identified in human plasma following norethisterone administration, all requiring enzymatic conversion before elimination 4.
Route of Excretion
Metabolites are primarily excreted renally after hepatic transformation, rather than the parent compound being eliminated unchanged 3, 4.
When administered transdermally, norethisterone avoids hepatic first-pass metabolism initially but still requires metabolic transformation for ultimate elimination from the body 5.
Clinical Implications for Organ Dysfunction
Hepatic function is more critical than renal function for norethisterone elimination, similar to drugs like haloperidol that are predominantly hepatically metabolized 6.
Patients with severe liver dysfunction may experience reduced clearance of norethisterone, as approximately 75% of related progestins like rimantadine undergo hepatic metabolism 1.
The 7α-methyl substitution in some norethisterone derivatives inhibits 5α-reductase, preventing formation of certain metabolites and altering the elimination profile 3.
Metabolic Considerations
Enzymatic hydrolysis is required before norethisterone metabolites can be detected and measured in plasma, indicating conjugated forms are present in circulation 4.
The metabolism produces both active and inactive metabolites, with 5α-reduction paradoxically enhancing androgen receptor binding while diminishing androgenic potency 7.