The clinical effect and the risk of experiencing adverse events is unpredictable in patients using the glucose lowering drug metformin and the opioid morphine. Due to their physiochemical properties both drugs rely on drug transporters for their entry into cells. Genetic variation and/or drug-drug interactions in these transporters may well affect the drugs pharmacokinetics and thereby contribute to the interindividual variance seen in drug response. Metformin and morphine are both substrates of the organic cation transporter 1 (OCT1) while the prodrug codeine is an inhibitor. Results from epidemiological studies have indicated that concomitant use of codeine and metformin increases the risk of metformin related intolerance. We hypothesize that this can be explained by a pharmacokinetic interaction between these drugs at the transporter level. Further, genetic variation in OCT1 may determine the distribution of morphine and hence have an impact on the analgesiceffect and magnitude of adverse events. The thesis is based on results from three different pharmacokinetictrials.
Study 1Common genetic variants in OCT1, OCT2 and multidrug and toxin extrusion transporters 1 and 2 (MATE1and 2), which are the most extensively researched genes coding for drug transporters involved in metformindisposition, has not shown to have any statistically significant effect on the glucose lowering effect of thedrug. Therefore, there is a need to investigate other candidate genes. The main objective of the first study wasto demonstrate that the already validated limited sampling strategy (LSS) used in healthy volunteers in apharmacogenetic, prospective setting produces a similar metformin area under the concentration time curve(AUC0-24h) and renal clearance (CLrenal) as previous results obtained from a full pharmacokinetic dataset. Inbrief, our results showed substantial interindividual variance in the pharmacokinetic parameters as well asthey further supported the feasibility for using a LSS in large prospective pharmacogenetic trials as themedian metformin AUC0-24h and CLrenal were in line with previous results.
Study 2The main objective of the second study was to investigate if there is a clinically relevant drug-drug interactionbetween metformin, codeine, and morphine in healthy volunteers genotyped as Cytochrome P450 2D6(CYP2D6) normal metabolizers (*1/*1), without common genetic variants in OCT1 (rs12208357, rs34130495,rs34059508, rs72552763) known to reduce metformin uptake. In brief, codeine did not have a clinicallyrelevant impact on the pharmacokinetics of orally or intravenously administered metformin. Oral andintravenous metformin resulted in a small increase in the AUC of morphine and its metabolites, morphine-3-glucuronide (M3G) and the pharmacologically active morphine-6-glucuronide (M6G). Even minor changes inmorphine plasma concentrations are known to be of importance for the risk of experiencing morphine relatedadverse events and the impact may be even greater in individuals with known risk factors for experiencingmorphine related adverse events, such as high age and female sex. Hence, a clinically relevant drug interactionseems probable.
Study 3The main objective of the third study was to determine the AUC0-1.5h for morphine, M3G and M6G in patientsundergoing major surgery with different numbers of loss-of-function alleles in OCT1. We observed that lossof-function alleles in OCT1 had a small but clinically insignificant impact on the exposure of morphine, M3Gand M6G following an intravenous bolus of morphine. Further, the genetic variants had no impact on theexperience of pain, adverse events, or the number of patient-controlled analgesia (PCA) doses used.
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