Hydromorphone, pharmacokinetics

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. 

Pharmacokinetic properties Hydromorphone (Hagen et al.,1995) is rapidly but incompletely absorbed from the gastrointestinal tract. It is metabolized in the gut and liver... 

Hagen, N., Thirlwell, M.P., Dhaliwal, H.S., Babul, N., Harsanyi, Z., Darke, A.C. Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone, J. Clin. Pharmacol. 1995, 35, 37-44. 

Vasili, V., S. Harris, A. El-Tahtawy, D. Wu, et al., Clinical pharmacology and pharmacokinetics of once-daily hydromorphone hydrochloride extended-release capsules, J. Clin. Pharmacol., 45(5), 547-554, 2005. 

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. 

For morphine, hydromorphone, and oxymorphone, rectal administration is an alternate route for patients unable to take oral medications, but equianalgesic doses may differ from oral and parenteral doses because of pharmacokinetic differences. 

Pharmacokinetic data in healthy subjects has shown that consuming alcohol with a particular 24-hour extended-release formulation of hydromorphone (Palladone XL Capsules Purdue Pharma, USA) could lead to rapid release (dose dumping) and absorption of a potentially fatal dose of hydromorphone. Although no reports of serious problems had been re-... 

The US manufacturer of hydromorphone says that the concurrent use of H2-receptor antagonists (cimetidine, famotidine, ranitidine) had no significant effect on hydromorphone steady-state pharmacokinetics. ... 

Inturrisi C, Portenoy R, Stillman M, et al. Hydromorphone bioavailability and pharmacokinetic-pharmacodynamic relationships. Clin Pharm Ther 1988 43 162-169. 

Brose WG, Tanelian DL, et al. CSF blood pharmacokinetics of hydromorphone and morphine following lumbar epidural administration. Pain 1991 45 11-15. 

Palladone capsules are formulated using a con-trolled-release melt extrusion technology combining hydromorphone HCl with polymers to form pellets, which are then loaded into gelatin capsules. The capsules are designed to provide uniform, controlled release of hydromorphone over a 24 hour period and are produced in 12,16,24, and 32 mg dosages. Pharmacokinetic studies of Palladone demonstrated that a steady-state level is reached in 2 to 3 days and the formulation has an elimination half-life of approximately 18.6 hours. 

Figure 112.2. The pharmacokinetic profiie of Paiiadone shows that at steady-state this formuiation provides a constant therapeutic ievei of drug with iess pronounced peak and trough ieveis compared to immediate-reiease hydromorphone,...

SathyanG, Xu E,Thipphawongl, Gupta SK. Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence and absence of food. BMC Clin Pharmacol 2007 7 2. 

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]. 

---