Clearance of codeine

Codeine (7.1) is an analgesic that may be administered by an IV bolus (Figure 7.4). A typical therapeutic Cp value for codeine is 200 ng/mL, and the hepatic extraction ratio (Eh) for codeine is 0.50. The clearance of codeine (CEp) is reported to be around 10.7 mL/min/kg, or 750 mL/min, in a 70-kg patient. Codeine is not observed in the urine of patients, so ER must be 0, and renal clearance (CER) is 0 mL/min. As a result, hepatic clearance of codeine (CEH) is equal to total clearance. Because codeine is cleared only by the liver, codeine provides a simple illustration of the ideas surrounding clearance. 

A similar example to azithromycin, but in a small molecule series is pholcodine (Figure 4.10), where a basic morpholino side chain replaces the methyl group of codeine. Unbound clearance is essentially similar (10 mL min" kg" ) but the free unbound volume is increased approximately 10-fold (4 to 40 L kg" ) with a corresponding increase in half-life (3 to 37 h) [16]. 

Opiates can effect serum levels of enzymes and other substances whose homeostatic control depends on clearance through the liver (F8, G12, M15, N4, S19). In one reported case, the aspartate aminotransferase was within normal limits before the administration of codeine, but within 2 hours after the drug, the enzyme activity had risen to two times the normal value by 8 hours to eight times the normal activity, and within 24 hours it had returned to normal (F8). Increases in transaminase to levels 5-85 times the control value have been reported in 6 of 16 patients with disease of the biliary tree following the administration of codeine phosphate (2 grains) (B7, F8). Gross has shown that morphine, codeine, or mepheridine administration produce elevations of serum amylase or lipase (G12). These elevations have been attributed to constriction of the sphincter of Oddi and increased intraductal pressure on the pancreatic duct (G12, N4). 

There is a scarcity of clinical trials regarding the use of codeine and dihydrocodeine in liver impairment however, they are both metabolised via similar pathways to morphine and dihydromorphine, respectively, and as morphine has been shown to have reduced clearance in cirrhosis the same could be expected of codeine and dihydrocodeine. 

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. 

After oral administration, concentrations of propoxyphene peak at 1-2 hours. There is great variability between subjects in the rate of clearance average t ofpropoxyphene in plasma after a single dose is 6-12 hours, which is longer than that of codeine. In humans, the major route of metabolism is H-demethylation to yield norpropoxyphene, which has a t of 30 hours and may accumulate to toxic levels with repeated doses. 

A single 50-mg dose of diclofenac sodium did not have an important effect on the pharmacokinetics of a single 100-mg dose of codeine phosphate in a placebo-controlled crossover study in 12 healthy subjects. There was no effect on the metabolic clearance of morphine, and only a slight (about 5% to 10%) increase in the levels of glucuronide metabolites. In addition, diclofenac did not alter the analgesic effects of codeine as assessed in a cold pressor test (a test in which opioids, but not NSAIDs, are effective). ... 

Sonne J, Poulsen HE, Loft S, Dossing M, Vollmer-Larsen A, Simonsen K, Thyssen H, Lund-stmm K. Therapeutic doses of codeine have no effect on acetaminq>hen clearance or metabolism. EurJC/wP [Pg.196]

There are approximately 100 CYP2D6 allelic variants identified however, there are basically four metabolizer states poor metabolizers (PM), who have two inactive genes and have no enzymatic activity intermediate metabolizers (IM), who have less than normal activity, usually one inactive and one low-activity gene extensive metabolizers (EM), who have one or two wild-type genes and ultrarapid metabolizers (UM), who possess more than two wild-type genes and increased enzymatic activity. These genetic variations may account for the differences in intrinsic clearance of 70-fold between EM and PM for codeine 0-demethylation, 10-fold for dihydrocodeine and oxycodone and 200-fold for hydrocodone. 

In the discovery phase, metabolite identification is usually performed with a combination of in vitro and in vivo experiments using samples from different species in order to compare metabolite exposures. The structural identification of major circulating metabolites formed in nonclinical animal models as well as the metabolites formed in human in vitro systems is needed for the metabolites to be synthesized and their pharmacological activities and/or toxicological implications to be determined [25], In addition, metabolite identification can lead to the discovery of candidates with satisfactory clearance/PK properties and/or improved safety profile. Following are some examples of metabolites that were later developed as drugs desloratadine from loratadine, acetaminophen from phenacetin, morphine from codeine, minoxidil sulfate from minoxidil, fexofenadine from terfenadine, and oxazepam from diazepam. 

Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain terminator that is extensively glucuronidated (70% of the dose) primarily by UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir, tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone (McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7 substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate (Lertora, 1994). Rifampin increased the formation clearance to AZT-glucuronide by twofold (Gallicano, 1999). 

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