Pharmacokinetics of Phentermine
Absorption and Peak Concentration
Phentermine reaches peak plasma concentrations (Cmax) 3 to 4.4 hours after oral administration 1. The drug is available as both immediate-release formulations and as a resin complex, with the resinates showing considerably slower absorption compared to the hydrochloride salt 2.
Distribution
The apparent central volume of distribution (Vc/F) has been characterized in clinical studies, with values in adolescents with obesity falling within 10-30% of those observed in adults 3. Phentermine hydrochloride is a readily soluble salt that distributes systemically following absorption 2.
Metabolism
Phentermine undergoes minimal biotransformation, with the drug being excreted largely unchanged 2. The primary metabolic pathways include:
- p-hydroxyphentermine - a primary metabolite 2
- N-hydroxyphentermine - a primary metabolite 2
- Both metabolites are also excreted as glucuronide conjugates 2
The limited metabolism distinguishes phentermine from more extensively metabolized sympathomimetic amines and contributes to its pharmacokinetic profile.
Elimination
Cumulative urinary excretion of unchanged phentermine ranges from 62% to 85% under uncontrolled urinary pH conditions 1. This high renal excretion of unchanged drug underscores the importance of renal function in phentermine clearance.
Effect of Urinary pH
Acidification of the urine increases phentermine excretion 1. This pH-dependent elimination is clinically relevant in overdose management and explains variability in drug clearance between individuals.
Apparent Clearance
The apparent clearance (CL/F) remains consistent across dose levels and is comparable between adolescents and adults with obesity 3. Terminal elimination half-life values are also consistent across different dose levels 3.
Renal Impairment Effects
Systemic exposure to phentermine increases substantially in patients with renal impairment 1:
- Severe renal impairment: up to 91% increase in exposure 1
- Moderate renal impairment: 45% increase in exposure 1
- Mild renal impairment: 22% increase in exposure 1
These significant increases necessitate dose adjustments in patients with compromised renal function to avoid excessive drug accumulation and potential toxicity.
Drug Interactions Affecting Kinetics
When co-administered with topiramate, phentermine Cmax increases by 13% and AUC increases by 42% 1. In contrast, phentermine does not significantly affect topiramate exposure 1. This interaction is relevant for the fixed-dose combination products containing both agents.
Pharmacodynamic Considerations
Tachyphylaxis and tolerance have been demonstrated with phentermine and related drugs of this class 1. This phenomenon contributes to the recommendation for short-term use, as the drug's effectiveness may diminish over time despite continued therapeutic plasma concentrations.
Clinical Implications
The pharmacokinetic profile of phentermine—characterized by minimal metabolism, predominantly renal excretion, and pH-dependent elimination—has several practical implications:
- Renal function must be assessed before initiating therapy, with dose reductions required in patients with impairment 1
- Drug interactions primarily occur at the pharmacodynamic level rather than through metabolic pathways, though the topiramate interaction demonstrates kinetic effects 1
- The 3-4 hour time to peak concentration supports once-daily morning dosing to minimize insomnia risk 4