Carboxylesterase 1 c.428G>A single nucleotide variation increases the antiplatelet effects of clopidogrel by reducing its hydrolysis in humans.

Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. We studied the pharmacokinetics and pharmacodynamics of 600 mg oral clopidogrel in healthy white volunteers, including 10 carriers and 12 noncarriers of CES1 c.428G>A (p.Gly143Glu, rs71647871) single nucleotide variation (SNV). Clopidogrel carboxylic acid to clopidogrel area under the plasma concentration-time curve from 0 hours to infinity (AUC0-∞ ) ratio was 53% less in CES1 c.428G>A carriers than in noncarriers (P = 0.009), indicating impaired hydrolysis of clopidogrel. Consequently, the AUC0-∞ of clopidogrel and its active metabolite were 123% (P = 0.004) and 67% (P = 0.009) larger in the c.428G>A carriers than in noncarriers. Consistent with these findings, the average inhibition of P2Y12 -mediated platelet aggregation 0-12 hours after clopidogrel intake was 19 percentage points higher in the c.428G>A carriers than in noncarriers (P = 0.036). In conclusion, the CES1 c.428G>A SNV increases clopidogrel active metabolite concentrations and antiplatelet effects by reducing clopidogrel hydrolysis to inactive metabolites.

Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions.

Cerivastatin and repaglinide are substrates of cytochrome P450 (CYP)2C8, CYP3A4, and organic anion-transporting polypeptide (OATP)1B1. A recent study revealed an increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel, warranting further studies on clopidogrel interactions. In healthy volunteers, repaglinide area under the concentration-time curve (AUC(0-∞)) was increased 5.1-fold by a 300-mg loading dose of clopidogrel and 3.9-fold by continued administration of 75 mg clopidogrel daily. In vitro, we identified clopidogrel acyl-ß-D-glucuronide as a potent time-dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl-ß-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl-ß-D-glucuronide at the CYP2C8 active site with its thiophene moiety close to heme. The results indicate that clopidogrel is a strong CYP2C8 inhibitor via its acyl-ß-D-glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes.

Grapefruit juice inhibits the metabolic activation of clopidogrel.

Cytochrome P450 (CYP) enzymes, including CYP2C19 and CYP3A4, participate in the bioactivation of clopidogrel. Grapefruit juice constituents potently inactivate intestinal CYP3A4 and have been shown to inhibit CYP2C19 as well. In a randomized crossover study, 14 healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 3 days. On day 3, they ingested a single 600-mg dose of clopidogrel. Grapefruit juice reduced the peak plasma concentration (Cmax) of the active metabolite of clopidogrel to 13% of the control (range 11-17%, P < 0.001) and the area under the plasma concentration-time curve from 0 to 3 h to 14% (range 12-17%, P < 0.001) of the control, but it had no significant effect on the parent clopidogrel. Moreover, grapefruit juice markedly decreased the platelet-inhibitory effect of clopidogrel, as assessed with the VerifyNow P2Y12 test in two of the participants. In conclusion, concomitant use of grapefruit juice may impair the efficacy of clopidogrel. Therefore, the use of grapefruit juice is best avoided during clopidogrel therapy.

Gemfibrozil impairs imatinib absorption and inhibits the CYP2C8-mediated formation of its main metabolite.

Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-∞) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0-∞ of imatinib was unaffected. Furthermore, gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption.

Carboxylesterase 1 polymorphism impairs oseltamivir bioactivation in humans.

Bioactivation of the antiviral agent oseltamivir to active oseltamivir carboxylate is catalyzed by carboxylesterase 1 (CES1). After the screening of 860 healthy Finnish volunteers for the CES1 c.428G>A (p.Gly143Glu, rs121912777) polymorphism, a pharmacokinetic study with 75 mg oseltamivir was carried out in c.428G>A carriers and noncarriers. Heterozygous c.428GA carriers (n = 9) had 18% larger values of oseltamivir area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) (P = 0.025) and 23% smaller carboxylate-to-oseltamivir AUC(0-∞) ratio (P = 0.006) than noncarriers (n = 12). This shows that the CES1 c.428G>A polymorphism impairs oseltamivir bioactivation in humans.

Gemfibrozil is a strong inactivator of CYP2C8 in very small multiple doses.

Therapeutic doses of gemfibrozil cause mechanism-based inactivation of CYP2C8 via formation of gemfibrozil 1-O-ß-glucuronide. We investigated the extent of CYP2C8 inactivation caused by three different doses of gemfibrozil twice dailyfor 5 days, using repaglinide as a probe drug, in 10 healthy volunteers. At the end of this 5-day regimen, there were dose-dependent increases in the area under the plasma concentration­time curve from 0 to infinity (AUC0­∞) of repaglinide by3.4-, 5.5-, and 7.0-fold corresponding to 30, 100, and 600 mg of gemfibrozil, respectively, as compared with the control phase (P < 0.001). On the basis of a mechanism-based inactivation model involving gemfibrozil 1-O-ß-glucuronide, a gemfibrozil dose of 30 mg twice daily was estimated to inhibit CYP2C8 by >70% and 100 mg twice daily was estimated to inhibit it by >90%. Hence, gemfibrozil is a strong inactivator of CYP2C8 even in very small, subtherapeutic, multiple doses. Administration of small gemfibrozil doses may be useful in optimizing the pharmacokinetics of CYP2C8 substrate drugs and in reducing the formation of their potentially toxic metabolites via CYP2C8.

Local infiltration analgesia with levobupivacaine compared with intrathecal morphine in total hip arthroplasty patients.

BACKGROUND: Recently, local infiltration analgesia (LIA) has been promoted for pain control after total hip arthroplasty (THA). We hypothesized that LIA would offer equal analgesic efficacy but less adverse effects, e.g., nausea and vomiting, when compared with an established regimen [intrathecal morphine (it-M)] after THA. METHODS: This randomized controlled trial comprised 60 patients undergoing THA under spinal anaesthesia. For LIA, the surgeon administered levobupivacaine, ketorolac and epinephrine at the surgical site intraoperatively. LIA patients received a LIA top-up through a wound catheter on the morning of the 1st post-operative day (POD). In group it-M, 0.1 mg morphine was given together with the spinal anaesthetic. Study parameters included pain scores, vital parameters and side effects, e.g., post-operative nausea and vomiting (PONV). Besides, levobupivacaine plasma concentrations were determined in 10 LIA patients. RESULTS: The median (25th/75th percentiles) rescue oxycodone demand differed significantly with LIA 15 (10/25) mg vs. 8.5 (1.5/15) mg with it-M (P < 0.006) during the day of surgery, but not anymore on 1st or 2nd POD. The LIA top-up had no effect. However, both analgesic regimens resulted in comparable pain scores and patient satisfaction. PONV incidence and medication did not vary significantly. LIA offered certain advantages regarding early post-operative mobilization. Maximum levobupivacaine plasma concentrations (229-580 ng/ml) remained under the toxic level. CONCLUSIONS: While LIA might enable earlier mobilization after THA, it was not associated with less nausea as compared with it-M. Less rescue oxycodone was given early after it-M, but urinary retention was more common in that group.

Effect of intravenous lipid emulsion on bupivacaine plasma concentration in humans.

Intravenous lipid emulsion is the recommended treatment for severe local anaesthetic intoxication. Lipid emulsion may entrap lipid soluble drugs by functioning as a 'lipid sink', but its effect on bupivacaine pharmacokinetics remains unknown. In this randomised, double-blind, crossover study, eight healthy male volunteers were infused bupivacaine 0.5mg.kg(-1) intravenously over 20 min, followed by an infusion of either intravenous lipid emulsion or Hartmann's solution for 30 min. At 20 and 30 min after the start of the infusion, the total plasma bupivacaine concentration was lower while receiving lipid emulsion than Hartmann's solution (mean difference 111 (95% CI 55-167) µg.l(-1) and 75 (95% CI 26-124 µg.l(-1) at 20 and 30 min, respectively; p<0.02). However, there were no differences in un-entrapped (non-lipid bound) or free (non-protein bound) bupivacaine plasma concentrations during the infusion. Intravenous lipid emulsion infusion reduced the context-sensitive half-life of total plasma bupivacaine from 45 (95% CI 32-76)min to 25 (95% CI 20-33)min; p=0.01. We observed no significant adverse effects of lipid emulsion. In conclusion, lipid emulsion may slightly increase the rate of bupivacaine tissue distribution. No 'lipid sink' effect was observed with the non-toxic dose of bupivacaine used.

Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates.

BACKGROUND AND PURPOSE: Imatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Because competitive inhibition of CYP3A4/5 does not explain these in vivo interactions, we investigated the reversible and time-dependent inhibitory effects of imatinib and its main metabolite N-desmethylimatinib on CYP2C8 and CYP3A4/5 in vitro. EXPERIMENTAL APPROACH: Amodiaquine N-deethylation and midazolam 1'-hydroxylation were used as marker reactions for CYP2C8 and CYP3A4/5 activity. Direct, IC(50) -shift, and time-dependent inhibition were assessed with human liver microsomes. KEY RESULTS: Inhibition of CYP3A4 activity by imatinib was pre-incubation time-, concentration- and NADPH-dependent, and the time-dependent inactivation variables K(I) and k(inact) were 14.3 µM and 0.072 in(-1) respectively. In direct inhibition experiments, imatinib and N-desmethylimatinib inhibited amodiaquine N-deethylation with a K(i) of 8.4 and 12.8 µM, respectively, and midazolam 1'-hydroxylation with a K(i) of 23.3 and 18.1 µM respectively. The time-dependent inhibition effect of imatinib was predicted to cause up to 90% inhibition of hepatic CYP3A4 activity with clinically relevant imatinib concentrations, whereas the direct inhibition was predicted to be negligible in vivo. CONCLUSIONS AND IMPLICATIONS: Imatinib is a potent mechanism-based inhibitor of CYP3A4 in vitro and this finding explains the imatinib-simvastatin interaction and suggests that imatinib could markedly increase plasma concentrations of other CYP3A4 substrates. Our results also suggest a possibility of autoinhibition of CYP3A4-mediated imatinib metabolism leading to a less significant role for CYP3A4 in imatinib biotransformation in vivo than previously proposed.

Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study.

BACKGROUND: Oxycodone is a µ-opioid receptor agonist, the global use of which has increased vigorously during the past decade. The pharmacokinetic data of oxycodone available for elderly are limited, and there appear to be only little data on the population pharmacokinetics of oxycodone. METHODS: We analysed 1272 plasma oxycodone samples of 77 individuals (range of age 19-89 yr) with non-linear mixed effect modelling. Inter- and intra-individual variability of the model was estimated for clearances and distribution volumes. The effect of covariates was studied with simulations. RESULTS: Data were best described with a two-compartment linear model. Lean body mass and age were found to be significant covariates for elimination clearance and the volume of the central compartment. The population estimates of elimination clearance, volume of the central compartment, and the volume of distribution at steady state for a reference individual (male 35 yr, 70 kg, 170 cm) were 51.0 litre h(-1), 134, and 258 litres, respectively. The elimination half-life of oxycodone showed an age-dependent increase. The context-sensitive half-time at steady state increased from 3.8 to 4.6 h between the age of 25 and 85 yr, respectively. Simulations of repetitive bolus dosing showed a 20% increase in oxycodone concentration in the elderly. CONCLUSIONS: Age was found to be a significant covariate for oxycodone pharmacokinetics. In elderly patients, dosing should therefore be reduced and carefully titrated to avoid considerable accumulation of oxycodone and potentially hazardous side-effects.

A mechanistic, model-based approach to safety assessment in clinical development.

Assessing the safety of pharmacotherapies is a primary goal of clinical trials in drug development. The low frequency of relevant side effects, however, often poses a significant challenge for risk assessment. Methodologies allowing robust extrapolation of safety statistics based on preclinical data and information from clinical trials with limited numbers of patients are hence needed to further improve safety and efficacy in the drug development process. Here, we present a generic systems pharmacology approach integrating prior physiological and pharmacological knowledge, preclinical data, and clinical trial results, which allows predicting adverse event rates related to drug exposure. Possible fields of application involve high-risk populations, novel drug candidates, and different dosing scenarios. As an example, the approach is applied to simvastatin and pravastatin and the prediction of myopathy rates in a population with a genotype leading to a significantly increased myopathy risk.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e13; doi:10.1038/psp.2012.14; advance online publication 7 November 2012.

Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine.

This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine.

Mechanism-based inactivation of CYP2C8 by gemfibrozil occurs rapidly in humans.

To study the time to onset of mechanism-based inactivation of cytochrome P450 (CYP) 2C8 by gemfibrozil in vivo, we conducted a randomized five-phase crossover study in 10 healthy volunteers. In one phase the volunteers ingested 0.25 mg of repaglinide alone (control), and in the other phases they received 600 mg of gemfibrozil 0-6 h prior to the repaglinide dose. When gemfibrozil was taken 0, 1, 3, or 6 h before repaglinide, the geometric mean ratio relative to control (90% confidence interval (CI)) of repaglinide area under the plasma concentration-time curve (AUC(0-∞)) was 5.0-fold (4.3-5.7-fold), 6.3-fold (5.4-7.5-fold), 6.6-fold (5.6-7.7-fold), and 5.4-fold (4.8-6.1-fold), respectively (P < 0.001 vs. control). The geometric mean ratio relative to control (90% CI) of the maximum plasma concentration (C(max)) of the CYP2C8-mediated metabolite M4 was 1.0-fold (0.8-1.3-fold), 0.10-fold (0.06-0.17-fold, P < 0.001), 0.06-fold (0.04-0.10-fold, P < 0.001), and 0.09-fold (0.05-0.14-fold, P < 0.001), respectively. The strong inactivation of CYP2C8, evident as soon as 1 h after gemfibrozil dosing, has implications in clinical practice and in studies with gemfibrozil as a CYP2C8 model inhibitor.

Dexmedetomidine inhibits gastric emptying and oro-caecal transit in healthy volunteers.

BACKGROUND: Dexmedetomidine is a potent and selective α2-adrenoceptor agonist used for perioperative and intensive care sedation with certain beneficial qualities. However, based on preclinical observations, it might inhibit gastric emptying and gastrointestinal transit, which could result in unwanted effects in intensive care patients. This study evaluated the effects of dexmedetomidine on gastric emptying and oro-caecal transit time in healthy volunteers. METHODS: Twelve healthy male subjects were given 1 µg kg(-1) of dexmedetomidine i.v. over 20 min followed by a continuous i.v. infusion of 0.7 µg kg(-1) h(-1) for 190 min. For comparison, subjects were also given 0.10 mg kg(-1) of morphine hydrochloride i.v. over 20 min and a placebo infusion in a randomized order. Gastric emptying was assessed with the paracetamol absorption test and oro-caecal transit time with the hydrogen breath test. RESULTS: The time to maximum paracetamol concentration in plasma was significantly longer, maximum paracetamol concentration was significantly lower, the area under the plasma paracetamol concentration-time curve was significantly smaller, and oro-caecal transit time was significantly longer during dexmedetomidine infusion compared with morphine or placebo infusion. CONCLUSIONS: Dexmedetomidine markedly inhibits gastric emptying and gastrointestinal transit in healthy volunteers.

Plasma levels of bupivacaine and its metabolites after subacromial infusions in concentrations 2.5 or 5.0 mg/ml.

BACKGROUND: We studied plasma bupivacaine concentrations in patients with a continuous subacromial bupivacaine infusion after an ambulatory arthroscopic shoulder surgery to evaluate whether it is feasible to discharge patients with an on-going infusion early on the operation day. METHODS: Sixteen ASA I-III patients undergoing elective arthroscopic shoulder surgery were randomized in 1:1 ratio to receive a continuous infusion of either 2.5 or 5.0 mg/ml bupivacaine subacromially for 48 h post-operatively. Before the commencement of the infusion, 20 ml of 5.0 mg/ml bupivacaine was injected subacromially in both groups. Plasma bupivacaine concentrations were defined as the primary endpoint and concentrations of its metabolites, side effects and pain scores as the secondary endpoints. RESULTS: The mean total plasma bupivacaine concentration increased up to 48 h, the highest mean being 0.87 (SD 0.30) µg/ml during the 5.0 mg/ml treatment and 0.24 (0.10) µg/ml during the 2.5 mg/ml bupivacaine treatment. After 48 h, there was a significant difference between the groups in the plasma levels. The highest mean 4-hydroxy-bupivacaine and desbutylbupivacaine concentrations were 0.11 and 0.22 µg/ml, respectively. In the pain scores, no significant difference was found. No clear signs of toxicity were observed. CONCLUSIONS: The concentrations of total bupivacaine and its metabolites remained below toxic levels. Excluding patients with renal or liver diseases, both 2.5 and 5.0 mg/ml bupivacaine as subacromial infusion 2 ml/h for 48 h following shoulder arthroscopy seem to be well tolerated, enabling patient discharge with an on-going infusion on the operation day. Because of similar side effects and pain scores in both groups, 2.5 mg/ml may be preferable.

Gemfibrozil markedly increases the plasma concentrations of montelukast: a previously unrecognized role for CYP2C8 in the metabolism of montelukast.

According to available information, montelukast is metabolized by cytochrome P450 (CYP) 3A4 and 2C9. In order to study the significance of CYP2C8 in the pharmacokinetics of montelukast, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 3 days, and 10 mg montelukast on day 3, in a randomized, crossover study. Gemfibrozil increased the mean area under the plasma concentration-time curve (AUC)(0-infinity), peak plasma concentration (C(max)), and elimination half-life (t(1/2)) of montelukast 4.5-fold, 1.5-fold, and 3.0-fold, respectively (P < 0.001). After administration of gemfibrozil, the time to reach C(max) (t(max)) of the montelukast metabolite M6 was prolonged threefold (P = 0.005), its AUC(0-7) was reduced by 40% (P = 0.027), and the AUC(0-24) of the secondary metabolite M4 was reduced by >90% (P < 0.001). In human liver microsomes, gemfibrozil 1-O-beta glucuronide inhibited the formation of M6 (but not of M5) from montelukast 35-fold more potently than did gemfibrozil (half-maximal inhibitory concentration (IC(50)) 3.0 and 107 micromol/l, respectively). In conclusion, gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.

Grapefruit juice greatly reduces the plasma concentrations of the OATP2B1 and CYP3A4 substrate aliskiren.

In a randomized crossover study, 11 healthy volunteers ingested 200 ml of grapefruit juice or water three times a day for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren. Grapefruit juice reduced aliskiren peak plasma concentration (C(max)) by 81% (range, 42-91%, P < 0.001), area under the plasma aliskiren concentration-time curve (AUC)(0-infinity) by 61% (range, 15-72%, P < 0.001), and elimination half-life (t(1/2)) from 26.1 to 23.6 h (P = 0.020). Therefore, concomitant use of aliskiren and grapefruit juice is best avoided.

Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients.

Oxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the µ-opioid receptor. However, its affinity for the µ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent µ-opioid receptor agonist by CYP2D6. However, CYP3A4 is quantitatively a more important metabolic pathway. Chronic pain patients often use multiple medications. Therefore it is important to understand how blocking or inducing these metabolic pathways may affect oxycodone induced analgesia. The aim of this study was to find out whether blocking CYP2D6 would decrease oxycodone induced analgesia in chronic pain patients. The effects of the antidepressant paroxetine, a potent inhibitor of CYP2D6, on the analgesic effects and pharmacokinetics of oral oxycodone were studied in 20 chronic pain patients using a randomized, double-blind, placebo-controlled cross-over study design. Pain intensity and rescue analgesics were recorded daily, and the pharmacokinetics and pharmacodynamics of oxycodone were studied on the 7th day of concomitant paroxetine (20 mg/day) or placebo administration. The patients were genotyped for CYP2D6, 3A4, 3A5 and ABCB1. Paroxetine had significant effects on the metabolism of oxycodone but it had no statistically significant effect on oxycodone analgesia or use of morphine for rescue analgesia. Paroxetine increased the dose-adjusted mean AUC0-12h of oxycodone by 19% (-23 to 113%; P = 0.003), and that of noroxycodone by 100% (5-280%; P < 0.0001) but decreased the AUC0-12 h of oxymorphone by 67% (-100 to -22%; P < 0.0001) and that of noroxymorphone by 68% (-100 to -16%; P < 0.0001). Adverse effects were also recorded in a pain diary for both 7-day periods (placebo/paroxetine). The most common adverse effects were drowsiness and nausea/vomiting. One patient out of four reported dizziness and headache during paroxetine co-administration, whereas no patient reported these during placebo administration (P = 0.0471) indicating that these adverse effects were due to paroxetine. No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine-oxycodone interaction, or analgesic effects were observed probably due to the limited number of patients studied. The results of this study strongly suggest that CYP2D6 inhibition does not significantly change oxycodone analgesia in chronic pain patients and that the analgesic activity of oxycodone is mainly due to the parent compound and that metabolites, e.g. oxymorphone, play an insignificant role. The clinical implication of these results is that induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors particularly if combined with CYP2D6 inhibitors or when administered to poor metabolizers of CYP2D6.

UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo.

The response to statins shows large interpatient variability. Atorvastatin delta-lactone is pharmacologically inactive but has been associated with toxicity. We investigated the role of UDP-glucuronosyltransferases (UGTs) in atorvastatin lactonization. In human liver microsomes, lactonization was correlated with UGT1A3 (r(s) = 0.61, P < 0.0001) but not with UGT1A1. Surprisingly, lactone formation was significantly higher in carriers of UGT1A1*28, an allele that is associated with lower UGT1A1 expression. We show that this inverse correlation is due to extensive linkage disequilibrium in the UGT1A locus and that several UGT1A3 haplotypes are associated with strong increases in UGT1A3 expression in vitro. Analyses of the pharmacokinetic parameters of atorvastatin and metabolites in genotyped volunteers confirmed that there is an increase in atorvastatin lactonization in carriers of UGT1A3*2 in vivo. The potential of UGT genotyping to identify patients who are at increased risk for failure of therapy and/or adverse effects of statins warrants further investigation.

ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin.

The ABCG2 c.421C>A single-nucleotide polymorphism (SNP) was determined in 660 healthy Finnish volunteers, of whom 32 participated in a pharmacokinetic crossover study involving the administration of 20 mg atorvastatin and rosuvastatin. The frequency of the c.421A variant allele was 9.5% (95% confidence interval 8.1-11.3%). Subjects with the c.421AA genotype (n = 4) had a 72% larger mean area under the plasma atorvastatin concentration-time curve from time 0 to infinity (AUC(0-infinity)) than individuals with the c.421CC genotype had (n = 16; P = 0.049). In participants with the c.421AA genotype, the rosuvastatin AUC(0-infinity) was 100% greater than in those with c.421CA (n = 12) and 144% greater than in those with the c.421CC genotype. Also, those with the c.421AA genotype showed peak plasma rosuvastatin concentrations 108% higher than those in the c.421CA genotype group and 131% higher than those in the c.421CC genotype group (P < or = 0.01). In MDCKII-ABCG2 cells, atorvastatin transport was increased in the apical direction as compared with vector control cells (transport ratio 1.9 +/- 0.1 vs. 1.1 +/- 0.1). These results indicate that the ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and, even more so, of rosuvastatin-potentially affecting the efficacy and toxicity of statin therapy.