Polymorphic CYP2D6 is the enzyme that activates the opioid analgesic tramadol by O-demethylation to its active metabolite O-demethyltramadol (M1). Our objective was to determine the opioid effects measured by pupillary response to tramadol of CYP2D6 genotyped volunteers in relation to the disposition of tramadol and M1 in plasma. Tramadol displayed phenotypic pharmacokinetics and it was possible to identify poor metabolizers (PM) with >99 % confidence from the metabolic ratio (MR) in a single blood sample taken between 2.5 and 24 h post-dose. Homozygous extensive metabolizers (EM) differed from PM subjects by an almost threefold greater (P=0.0014) maximal pupillary constriction (Emax). Significant correlations between the AUC and Cmax values of M1 versus pupillary constriction were found. The corresponding correlations of pharmacokinetic parameters for tramadol itself were weaker and negative. The strongest correlations were for the single-point metabolic ratios at all sampling intervals versus the effects, with rs ranging from 0.85 to 0.89 (p‹0.01). It is concluded that the concept of dual opioid/non-opioid action of the drug, though considerably stronger in EMs, is valid for both EM and PM subjects. This is the theoretical basis for the frequent use and satisfactory efficacy of tramadol in clinical practice when given to genetically non-selected population., O. Slanař, M. Nobilis, J. Květina, R. Mikoviny, T. Zima, J. R. Idle, F. Perlík., and Obsahuje biblografii a bibliografické odkazy
Portal-systemic shunting is an important circulatory abnormality in patients with liver cirrhosis. Glyceryl trinitrate (GTN) that is normally subject to first pass elimination, may exhibit higher bioavailability in these patients. This study compares the pharmacodynamic effects of GTN after peroral and sublingual administration for noninvasive assessment of shunting. Six control subjects and 15 patients with cirrhosis were studied after oral and sublingual application of 0.5 mg of GTN. Liver cirrhosis was complicated by portal hypertension in 7 of the patients and 4 patients had surgically implanted portocaval anastomosis. Digital plethysmography, which is highly sensitive and is essentially noninvasive in nature, was used to assess and compare the pharmacodynamic effects of GTN. The following values of the ratio of areas under the pharmacodynamic effects/time curve were obtained: 0.08±0.06 in healthy subjects, 0.52±0.21 in patients with uncomplicated cirrhosis, 0.99±0.34 in patients with portal hypertension and 1.24±0.43 in patients with portal-systemic shunts. We conclude that increased bioavailability of GTN reflects portal-systemic shunting and might be used providing that the pharmacodynamic data reflect both pharmacokinetic variability and the pharmacokinetic-pharmacodynamic interrelations., O. Slanař, J. Aubrecht, F. Perlík., and Obsahuje bibliografii
Genetic factors may contribute to the differential response to opioids. The aim of this study was to evaluate the association between polymorphisms of μ1-opioid receptor gene OPRM1 (rs1799971), and P-glycoprotein transporter gene ABCB1 (rs1045642, rs2032582), and piritramide efficacy under postoperative patient-controlled analgesia (PCA). In 51 patients, OPRM1 variant was associated with decreased efficacy in early postoperative period evidenced by sum of pain intensity difference in the 0-6 h postoperative period (SPID0-6), (F=3.27, p=0.029). Mean (SD) SPID0-6 was observed in the 118AA genotype 22.9 (6.1) mm, which was significantly higher from the 118GG genotype 10.0 (4.4) mm, p=0.006. The lowest cumulative dose was recorded in 118AA genotype 19.1 (9.8) mg, which was significantly less than in the 118GG genotype group 36.6 (6.1) mg, p=0.017. Opioid-induced adverse effects were observed in 11, 30, and 100 % of patients in 118AA, 118AG, and 118GG genotype groups, respectively (p<0.05). Piritramide efficacy and safety was not significantly affected by ABCB1 (rs1045642, rs2032582) polymorphisms. Variant OPRM1 118G allele is associated with decreased acute postoperative pain relief after piritramide. Decreased efficacy leads to higher drug consumption under PCA settings, which however, does not fully compensate insufficient pain relief, but increases incidence of adverse effects., O. Bartošová, O. Polanecký, F. Perlík, S. Adámek, O. Slanař., and Obsahuje bibliografii