Hydrocodone undergoes oxidative O-demethylation to form [hydromorphone], a more potent active metabolite. Though hydromorphone is active it is not present in sufficient quantities to contribute significantly to hydrocodone's therapeutic effects. Both hydrocodone and hydromorphone form 6-α- and 6-β-hydroxy metabolites through 6-ketoreduction. The hydroxy metabolites and hydromorphone can form glucuronide conjugates. Hydrocodone also undergoes oxidative N-demthylation to norhydrocodone. O-demethylation is primarily catalyzed by CYP2D6 while N-demethylation is primarily CYP3A4.
Like other phenanthrene derivatives, hydrocodone is probably metabolized in the liver and excreted mainly in urine. Metabolism of hydrocodone includes O-demethylation, N-demethylation, and 6-keto reduction.
Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-alpha- and 6-beta-hydroxymetabolites.
Following the administration of codeine 30 mg by mouth to 2 healthy subjects, hydrocodone, norhydrocodone, 6 alpha-hydrocodol, and 6 beta-hydrocodol in addition to known metabolites were detected in urine.
Pharmacokinetic drug-drug interactions with codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine are reviewed in this column. These compounds have a very similar chemical structure to morphine. Unlike morphine, which is metabolized chiefly through conjugation reactions with uridine diphosphate glucuronosyl transferase (UGT) enzymes, these five drugs are metabolized both through oxidative reactions by the cytochrome P450 (CYP450) enzyme and conjugation by UGT enzymes. There is controversy as to whether codeine, dihydrocodeine, and hydrocodone are actually prodrugs requiring activation by the CYP450 2D6 enzyme or UGT enzymes. Oxycodone and buprenorphine, however, are clearly not prodrugs and are metabolized by the CYP450 2D6 and 3A4 enzymes, respectively. Knowledge of this metabolism assists in the understanding for the potential of drug-drug interactions with these drugs. ...
IDENTIFICATION AND USE: Hydrocodone bitartrate (HD) is a phenanthrene-derivative opiate agonist antitussive and analgesic agent. HUMAN EXPOSURE AND TOXICITY: Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. A 3-year-old child died of the combined effects of a bacterial superinfection and a relative overdose of hydrocodone prescribed for a cough due to a presumed viral respiratory tract infection. Poison center rates of abuse and misuse were highest for hydrocodone at 3.75 per 100,000 population, followed by oxycodone at 1.81 per 100,000 population. DAWN emergency department (ED) data illustrate a similar pattern of abuse with most mentions involving hydrocodone and oxycodone. Poison center data indicate that people aged 18 to 25 had the highest rates of abuse. DAWN reported the majority of ED mentions among 35 to 44-year-olds. ANIMAL STUDIES: LD50 in rats was 150 mg/kg for sc administration and 375 mg/kg when given orally. HB was evaluated in rats (25/sex/group) and in rabbits (20 females/group) given daily po doses of 0 (Vehicle), 10, 33 and 100 mg/kg and 0 (Vehicle), 5.3, 16 and 48 mg/kg, respectively. Female rats were dosed gestation days (DGs) 7-17 and Cesarean-sectioned (CS) on DG 21 and female rabbits were dosed DGs 6-18 and CS on DG 29. Toxicokinetics was evaluated in the range-finding studies for both species at 0.5. 1, 2, 4, 6, 16 and 24 hr postdosage on the first and last days of dose administration. Survival was not affected in either species. Exaggerated pharmacological effects of HB and reduced body weight gain and absolute and relative feed consumption values were observed at all dosage levels in both studies. Rodent fetal body weights were reduced and a reduction in the number of ossifications sites for the caudal vertebrae, hindlimb phalanges and metatarsals occurred in the 100 mg/kg group. The number of late resorptions was increased in the 48 mg/kg group; no other CS parameters were affected and no gross, visceral or skeletal malformations attributed to HB. The maternal NOAELs were less than 10 mg/kg and 5.3 mg/kg for the rat and rabbit studies, respectively. The developmental NOAELs were 16 and 33 mg/kg for the rat and rabbit studies, respectively.
Hydrocodone acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Hydrocodone primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. Opioids such as hydrocodone also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
Despite wide scale use for many decades, hydrocodone by itself has not been convincingly linked to instances of clinically apparent acute liver injury. However, when combined with acetaminophen, hydrocodone combinations have become a common cause of acetaminophen acute liver injury. The typical history is of a patient who began taking more than the prescribed number of pills over several days, attempting to achieve more of an opiate effect and leading secondarily and unintentionally to an overdose of acetaminophen. Because of their potential for hepatotoxicity, opioid combinations in which the dose of acetaminophen is greater than 325 mg per tablet or capsule were discontinued.
Hydrocodone, like other opiates, is metabolized in the liver by the P450 microsomal oxidizing enzyme system, and levels can be significantly affected by either inhibitors of CYP 3A4 (which increase levels and can lead to toxicity) or inducers of the enzyme (which decrease levels and can affect efficacy).
Likelihood score: E (unlikely cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of hydrocodone are given in the Overview section of the Opioids.
Drug Class: Opioids
来源:LiverTox
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
健康影响
医学问题可能包括肺充血、肝病、破伤风、心脏瓣膜感染、皮肤脓肿、贫血和肺炎。过量可能会导致死亡。
Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.
The absolute bioavailability of hydrocodone has not been characterized due to lack of an IV formulation. The liquid formulations of hydrocodone have a Tmax of 0.83-1.33 h. The extended release tablet formulations have a Tmax of 14-16 h. The Cmax remains dose proportional over the range of 2.5-10 mg in liquid formulations and 20-120 mg in extended release formulations. Administration with food increases Cmax by about 27% while Tmax and AUC remain the same. Administration with 40% ethanol has been observed to increase Cmax 2-fold with an approximate 20% increase in AUC with no change in Tmax. 20% alcohol produces no significant effect.
Most hydrocodone appears to be eliminated via a non-renal route as renal clearance is substantially lower than total apparent clearance. Hepatic metabolism may account for a portion of this, however the slight increase in serum concentration and AUC seen in hepatic impairment indicates a different primary route of elimination.
The apparent volume of distribution ranges widely in published literature. The official FDA labeling reports a value of 402 L. Pharmacokinetic studies report values from 210-714 L with higher values associated with higher doses or single dose studies and lower values associated with lower doses and multiple dose studies. Hydrocodone has been observed in human breast milk at levels equivalent to 1.6% of the maternal dosage. Only 12 of the 30 women studied had detectable concentrations of hydromorphone at mean levels of 0.3 mcg/kg/day.
Official FDA labeling reports an apparent clearance of 83 L/h. Pharmacokinetic studies report values ranging from 24.5-58.8 L/h largely dependent on CYP2D6 metabolizer status.
HYSINGLA ER is a single-entity extended-release formulation of hydrocodone that yields a gradual increase in plasma hydrocodone concentrations with a median Tmax of 14 - 16 hours noted for different dose strengths. Peak plasma levels may occur in the range of 6 -30 hours after single dose HYSINGLA ER administration. Systemic exposure (AUC and Cmax) increased linearly with doses from 20 to 120 mg. Both Cmax and AUC increased slightly more than dose proportionally.
