Pharmacokinetics hydrocodone

Hydromorphone (I) and hydrocodone (II) belong to the morphine group of drugs and are used invariably in combination with other ingredients in a number of proprietory antitussive and analgesic antipyretic mixtures. However, interest in the pharmacokinetics of hydromorphone and hydrocodone in human subjects required an adequate assay for drug levels in plasma. 

Pharmacokinetic properties Hydrocodone is metabolized by CYP2D6 to the O-desmethyl derivative hydromorphone (Otton et al., 1993). Further steps of metabolization include N-demethylation and glucuronidation. 

A number of drugs of abuse are known substrates (e.g., codeine, hydrocodone, p-methoxyamphetamine, amphetamine) or inhibitors (e g., (-)-cocaine, pentazocine) of CYP2D6. For some of these drugs, the pharmacokinetic differences due to the polymorphism will be so profound that they are likely to exceed pharmacodynamic sources of variation in response. For other drugs (e.g., hydrocodone to hydromorphone, codeine to morphine, oxycodone to oxymorphone), CYP2D6 may not contribute importantly to the overall clearance of the drug, but may catalyze the formation of highly active metabolites. 

The analgesic effects of codeine, and probably also hydrocodone, are reduced or abolished by quinidine. Quinidine alters the pharmacokinetics of dihydrocodeine and oxycodone, but this does not appear to alter their effects. 

Hydrocodone has a half-life of 3.8 boms, peak effect at 1.3 hours, and a duration of 4.6 hours. It is metabolized by the liver and excreted primarily in urine. Hydrocodone is oxidized to hydromorphone by cytochrome P450 2D6. The extended-release formulation has measurably different pharmacokinetics following a single dose of 1,2 or 3 HC/ APAP CR tablet(s), the mean maximum plasma concentration (C ) ranged from 13.3 to 36.8 ng/mL for HC and 2.01 to 6.68 ng/mL for APAP. The mean time to reach (T ) was 6.0-6.7 hours for HC and 1.1-1.3 hours for APAP. Following twice-daily dosing of 2 HC/APAP CR tablets for 3 days, steady-state HC/APAP concentrations were attained by 24 hours [3,4]. The mean on day 3 was 37.0 ng/mL for HC and 4.96 ng/mL for APAP. Systemic exposures of HC and APAP demonstrated a dose-proportional increase from one to three tablets. Steady-state concentrations were reached by 24 hours with minimal accumulation following twice-daily administration. Thus, it can be taken every 12 hours [4]. 

Controlled-release HC/APAP is only formulated as an oral preparation containing a standard dose of hydro-morphone 15 mg and acetaminophen 500 mg, to be administered every 12 hours. Phase 3 study data indicate that 12-hour dosing provided effective pain relief for patients with moderate to severe acute and chronic pain. The drug should not be crushed or tampered with as that will change the pharmacokinetics of the extended-release hydrocodone. At this time, the manufacturer has not disclosed whether HC/APAP CR will be manufactured in a tamper-resistant formulation. 

Klein CE, Liu W, Qian JX, et al. Pharmacokinetics of 12-hour controUed-release hydrocodone and acetaminophen tablets in healthy subjects following single- and multiple-dose(s). The American Academy of Pain Medicine Annual Meeting, 23rd Annual Meeting, February 7-10,2007, New Orleans, LA. 

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