Naloxone is a synthetic narcotic antagonist and used for partial or complete reversal of opioid depression induced by natural or synthetic opioids. It has also been incorporated into oral tablets of opioids to discourage abuse. The duration of action is dependent on the dose and route of administration. The half-life in adults is approximately 30 to 81 minutes. This test reports the total urine concentration; this is the sum of the unconjugated and conjugated forms of the parent drug.
This test detects drugs structurally similar to morphine. Other drugs in the opioid class, such as fentanyl, meperidine, and methadone are not detected.
McGraw-Hill; chap Biomedical Publication; Ther Drug Monit. Elsevier; Skip to main content. Register Sign In. Test Catalog Account. Alcorn, J. Ontogeny of hepatic and renal systemic clearance pathways in infants: part II. Barter, Z. Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver.
Drug Metab. Brown, H. Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance.
Chiba, M. Prediction of hepatic clearance in human from in vitro data for successful drug development. AAPS J. DuBois, D. A formula to estimate the approximate surface area if height and weight be known.
CrossRef Full Text. Edginton, A. A mechanistic approach for the scaling of clearance in children. El-Tahtawy, A. Population pharmacokinetics of oxycodone in children 6 months to 7 years old. Falk, E. Eukodal, ein neues narkotikum. FDA Guidance for Industry. Rockville: Food and Drug Administration. Foster, J. Comparison of intrinsic clearances in human liver microsomes and suspended hepatocytes from the same donor livers: clearance-dependent relationship and implications for prediction of in vivo clearance.
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Demographic and sugery-related data as well as genotypes and pain scores were comparable to the oxycodone group Tables 2 — 4. This confirms our hypothesis and demonstrates that sufficiently high pain scores resulting in relevant analgesic needs are necessary to detect genotype dependent differences. However, its impact on analgesia is controversial since formation of oxymorphone is not considered the major metabolic pathway [18] , [22].
In a previous trial, plasma concentrations were measured 25 minutes after i. A decrease of oxymorphone concentrations and a shift to the N-demethylation pathway was reported in subjects with blocked CYP2D6 activity by comedication with quinidine , which resembles the PM status [23]. In contrast, the effect of paroxetine on plasma concentrations of one single i.
In these previous investigations, either no genotyping was performed or no sufficient number of subjects was enrolled to perform a genetic association study. The CYP3A4 pathway is described as quantitatively more important [18] with the N-demethylated metabolite noroxycodone showing poor antinociceptive effects [19] , [24] , [25]. CYP3A is the most abundant CYP protein in the human liver, and the influence of genetic variants on metabolism has been demonstrated in immunosuppressive drugs with a narrow therapeutic index and frequent side effects [26] — [28].
In contrast, data on other widely used drugs metabolized by CYP3A are sparse. For healthy volunteers, Samer and co-workers stated that oxycodone's pharmacokinetics is also modulated by CYP3A activity [29]. It is well described that comedication with voriconazole, itraconazole, telithromycin, rifampin or ketoconazol produces considerable changes in oxycodone's pharmacokinetic [2] , [3] , [29] — [33] and even foods like grapefruit juice can inhibit CYP3A activity with respective interactions [34].
Several authors have pointed out that dose adjustment of oxycodone might be necessary, when used concomitantly with CYP inducers or inhibitors to either maintain adequate analgesia or prevent overdosing [31] , [32].
However, data from large-scale clinical studies are lacking thus far. The central nervous system effects of oxycodone were described as governed by the parent drug, with a negligible contribution from its oxidative and reductive metabolites [18] , [22]. This hypothesis was mainly based on the low contribution of CYP2D6 to the overall metabolism of this opioid [18] , [22] , however, this hypothesis was not confirmed in all human trials.
Specifically in some volunteer studies, oxymorphone did play a role for analgesic efficacy in parallel to the clear-cut pharmacokinetic effects described in nearly all publications in which this issue has been addressed [1] , [13] , [29]. In experimental pain models enrolling a limited number of volunteers, oxycodone analgesia was reduced in PM compared to EM, whereas increased pharmacodynamic effects were described in two UM [13] , [29].
Some case reports [35] — [38] as well as the present results are in line with these findings. The overall low analgesic needs might have masked possible differences between genotypes. Stubhaug and co-workers stated that a sufficiently strong base-line pain is necessary to discriminate between drugs [39] or as in this case between different genotypes.
As hypothesized in the present trial, enrolling patients undergoing major surgery PM needed more oxycodone. A substantial change in the analgesic regimen for postoperative PCA seems not to be necessary as PM could compensate higher analgesic needs by demanding additional PCA bolus doses and titrating themselves to comfortable low pain intensities.
This is also reflected by comparable pain scores in the different CYP2D6 activity groups. The definition of equianalgesic doses of oxycodone to morphine has been described as difficult due to pharmacokinetic differences of the drugs [40]. In a further trial reporting a ratio of 1. Thus, possible differences in opioid potency may have been concealed. They are useful for clinicians in the case of opioid switching. Piritramide is the preferred opioid in a postoperative setting in several European countries due to rapid onset, absence of active metabolites, and unproblematic use, also in the case of impaired renal function [14] , [15].
There are some limitations in the current study. First, the overall number of patients included in this trial is limited. However, as the patients' genotypes were unknown during the clinical part of the trial and the drugs were administered via PCA by the patients themselves, the influence of physicians and nurses on analgesic consumption should be negligible.
For more detailed evaluation of genotype-associated oxycodone effects and side effects a larger patient cohort needs to be investigated in a future trial. Additionally, the influence of concomitant medication interfering with CYP activity has to be addressed in a postoperative setting. In this patient cohort recovering from major surgery and requiring clinically relevant opioid doses, a CYP2D6 genotype-dependent effect on plasma concentrations of oxycodone and oxymorphone was detected.
PCA technology overcomes differences in doses needed by various genotype groups, so that the PM also experienced sufficient pain relief from oxycodone in this postoperative setting. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field.
Abstract Background The impact of polymorphic cytochrome P CYP2D6 enzyme on oxycodone's metabolism and clinical efficacy is currently being discussed. Methods Patients received oxycodone 0. Conclusions In this postoperative setting, the number of functionally active CYP2D6 alleles had an impact on oxycodone metabolism. Funding: The authors have no support or funding to report.
Introduction While morphine represents the standard analgesic in a postoperative setting, other opioids might be also suitable or even advantageous. Methods Patients Approval for this prospective, observational association study was obtained from the institutional review board of the Medical Faculty of the University of Bonn.
Genotyping Blood samples were drawn at 30, 90 and minutes after opioid administration. Plasma Concentrations of Oxycodone and Its Metabolites Oxycodone, the metabolites oxymorphone, noroxycodone, and noroxymorphone as well as the deuterated standards oxycodone-d 3 , noroxycodone-d 3 , oxymorphone-d 3 and hydromorphone-d 3 were purchased from Cerilliant Corporation Round Rock, TX, USA. Download: PPT. Table 1. Statistical Analysis The primary study endpoint was the influence of CYP2D6 genotypes on metabolism and plasma concentrations of oxycodone and its metabolites.
Results Demographic Data and Genotypes In this trial, a total of patients were enrolled. Figure 1. Table 4. Demographic and Perioperative Data of Patients receiving Piritramide. Table 5. CYP3A Activity The CYP3A4 pathway is described as quantitatively more important [18] with the N-demethylated metabolite noroxycodone showing poor antinociceptive effects [19] , [24] , [25]. Genotype and Opioid Consumption The central nervous system effects of oxycodone were described as governed by the parent drug, with a negligible contribution from its oxidative and reductive metabolites [18] , [22].
Conclusions In this patient cohort recovering from major surgery and requiring clinically relevant opioid doses, a CYP2D6 genotype-dependent effect on plasma concentrations of oxycodone and oxymorphone was detected. References 1. Acta Anaesthesiol Scand — View Article Google Scholar 2. Br J Pharmacol — View Article Google Scholar 3. Clin Drug Investig —
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