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ABSTRACT: Drug disposition is altered by pregnancy and the peripartum period but data on intravenous ketorolac pharmacokinetics following caesarean delivery have not been previously reported.
At the end of caesarean delivery, women received an intravenous bolus of ketorolac tromethamine 30mg (immediate postpartum, Group IP). Plasma samples were collected at 1, 2, 4, 6 and 8h. A similar pharmacokinetic study was repeated in a subgroup of these women 4-5months after delivery (late postpartum, Group LP) and in a group of unrelated, healthy non-pregnant female volunteers (controls, Group C). A non-compartmental linear disposition model was applied to analyse individual ketorolac time-concentration profiles. Results at delivery were compared with controls using unpaired or paired statistics as appropriate. Covariates of pharmacokinetic estimates at delivery were examined.
Thirty-nine women were studied at caesarean delivery, of whom eight were re-evaluated 4-5months later. In addition, eight volunteers were studied. Clearance in Group IP was higher compared to Groups LP and C (2.11 vs. 1.43 and 1.07L/h·m(2) respectively, P<0.05). Volume of distribution was also increased in Group IP compared to Groups LP and C (0.24 vs. 0.16 and 0.17L/kg respectively, P<0.05). No significant covariates of pharmacokinetic estimates, including gestational age, preterm vs. term, twin vs. singleton and maternal co-morbidity, were seen in Group IP.
Ketorolac clearance and distribution volume are significantly increased following caesarean delivery. These data provide pharmacokinetic estimates on which to base studies on post caesarean analgesia.
International journal of obstetric anesthesia 08/2012; 21(4):334-8. · 1.85 Impact Factor
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ABSTRACT: Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830-4,200) g and a postmenstrual age (PMA) of 39 (25-45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10-0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R (2) = 0.39) had a slope significantly different from zero (p < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R (2) value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28-0.69) was significantly higher compared to the trough level (0.36, range 0.17-0.73) (p < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs.
European Journal of Clinical Microbiology 07/2012; · 2.86 Impact Factor
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ABSTRACT: The postpartum period affects drug disposition, but data of intravenous paracetamol loading dose pharmacokinetics immediately following caesarean delivery have not yet been reported.
Immediately following caesarean delivery, women received a 2-g loading dose of intravenous paracetamol. Plasma samples were collected at 1, 2, 4 and 6 h. Individual pharmacokinetics were calculated assuming a linear one-compartment model with instantaneous input and first-order output. Data were reported using median and range.
Twenty-eight patients undergoing caesarean delivery were recruited (age 31.5 [20-42] years, weight 79 [57-110] kg, body surface area 1.9 [1.5-2.4]m(2)). Median paracetamol plasma concentrations after 1, 2, 4 and 6 h were 22.5, 15.25, 7.9, and 3.9 mg/L respectively. Paracetamol clearance was 20.3 (11.8-62.8) L/h or 10.9 (7-23.8)L/hm(2), distribution volume 58.3 (42.9-156) L or 0.72 (0.52-1.56) L/kg.
Pharmacokinetics of intravenous paracetamol have been estimated following caesarean delivery. Although limited to a loading dose shortly after surgery, the results are clinically relevant since this is the first description in this patient population. These data provide evidence on which to base further integrated pharmacokinetic/pharmacodynamic studies in peripartum analgesia.
International journal of obstetric anesthesia 02/2012; 21(2):125-8. · 1.85 Impact Factor
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ABSTRACT: The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents.
Fluorouracil-epirubicin-cyclophosphamide (FEC) and doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25 h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide.
In nine baboons, at a median gestational age of 139 days (range, 93-169), FEC 100% (n = 2), FEC 200% (n=1), ABVD 100% (n = 5), and ABVD 200% (n = 1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5 ± 3.2% (n = 6) and 4.0 ± 1.6% (n = 8) of maternal concentrations, respectively. Fetal tissues contained 6.3 ± 7.9% and 8.7 ± 8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5 ± 15.5% (n=9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1 ± 6.3% (n = 3) and 63.0% (n = 1) of the maternal concentrations, respectively.
This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide.
Gynecologic Oncology 12/2010; 119(3):594-600. · 3.89 Impact Factor
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European Journal of Clinical Microbiology 10/2010; 30(2):283-7. · 2.86 Impact Factor
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ABSTRACT: /st> Propofol clearance is lower in neonates than in adults and displays extensive interindividual variability, in part explained by postmenstrual age (PMA) and postnatal age (PNA). Since propofol is almost exclusively cleared metabolically, urinary propofol metabolites were determined in early life and compared with similar observations reported in adults.
/st> Twenty-four hours urine collections were sampled after a single i.v. bolus of propofol (3 mg kg(-1)) in neonates undergoing procedural sedation. Clinical characteristics (PMA, PNA, weight, and cardiopathy) were recorded. Urine metabolites [propofol glucuronide (PG), 1- and 4-quinol glucuronide (QG)] were quantified using high-pressure liquid chromatography. Urine recovery (% administered dose) and the contribution of PG and QG to urinary elimination were calculated. Data were reported by median and range, analysed by Mann-Whitney U or Spearman's rank.
/st> Eleven neonates (median PNA 11 days, PMA 38 weeks) were included. Median propofol metabolite recovery was 64% (range 34-98%). PG contributed 34% (range 8-67%) and QG 65% (range 33-92%). There was no significant correlation between either PMA, PNA, or cardiopathy and propofol metabolites. Compared with adults, the contribution of PG (34% vs 77%) was lower and the contribution of QG (65% vs 22%) was higher in neonates.
/st> Propofol metabolism in neonates differs from adults, reflecting the age-dependent limited glucuronidation capacity. Hydroxylation to quinol metabolites already contributes to propofol metabolism. These differences likely explain the PMA- and PNA-dependent reduced propofol clearance in neonates.
BJA British Journal of Anaesthesia 10/2008; 101(6):827-31. · 4.24 Impact Factor
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ABSTRACT: A quantitative method for the simultaneous determination of theophylline (THP) and its metabolites, 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX), in urine is described, using a preliminary extraction step with ‘Extreluf column and high pressure liquid chromatographic separation. Urinary excretion data of theophylline and its metabolites from 2 healthy male volunteers on a regular diet demonstrated high background values of 1-MU, to a lesser degree for 3-MXandTHP, and virtually none for 1,3-DMU, when the subjects were not receiving theophylline. Observed increments {above background values) following single-dose (375 mg) administrations of theophylline, orally and rectally, demonstrated 1,3-DMU as the predominant urinary excretory product together with 3-MX as an additional urinary metabolite, while the virtual absence of any increments in the 1-MU metabolite would indicate that biotransformation of theophylline to the 1-MU pathway is minimal or insignificant after theophylline administration to subjects on a regular diet (possibly due to enzyme saturation associated with dietary methyl-xanthines). Similar excretion patterns of THP and its metabolites in urine after theophylline administrations, orally and rectally, suggest hepatic metabolism of theophylline after the two different routes of administration to be similar.
08/2008; 6(s6):151-160.
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ABSTRACT: Although of pharmacokinetic and -dynamic relevance, data on ontogeny of UDP-glucuronosyltransferase (UGT) activity in neonates are scant. We therefore wanted to assess the impact of both postnatal and postmenstrual age (PNA/PMA) on the interindividual variability of glucuronidation to overall tramadol urinary elimination in neonates.
O-demethyl tramadol (M1) and M1-glucuronide (M1G) were determined in 24 hour urine collections during continuous intravenous tramadol administration in neonates. Glucuronidation fraction (%) was calculated by the ratio of M1G to the sum of M1G and M1 free (M1total). Fractions (%) in early (<day 8) or late neonatal life (day 8-28) were compared (Mann-Whitney U) and forward multiple regression was applied to assess the impact of various covariates.
Urine collections were available in 59 neonates with a PNA of 6 (1-28) days and a PMA of 38 (SD 4) weeks. Mean M1G/M1total was 27 (SD 15) % and was significantly lower in early compared to late neonatal life (22 versus 32%, p=0.0001). In a forward multiple regression model, both PMA and early versus late neonatal life remained independent variables to explain the interindividual variability in M1G/M1total.
Besides PMA, there is an additional, independent impact of PNA since phenotypic glucuronidation activity is significantly lower in the first week of postnatal life. These findings should be taken into account in the assessment of compounds for whom glucuronidation is of pharmacokinetic, pharmacodynamic or toxicological relevance.
Early Human Development 06/2008; 84(5):325-30. · 2.05 Impact Factor
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ABSTRACT: Data on amniotic fluid (AF) disposition of cefazolin and its co-variates during pregnancy are limited. We therefore collected AF samples during in utero surgery in the second and third trimester of pregnancy and compared these observations with available data on AF disposition in very early pregnancy and at term gestation. During 45 in utero surgical interventions, 57 AF samples were collected. The median AF cefazolin concentration was 0.62 mg/l. Significant correlations between cefazolin concentration in AF and time after initiation of intravenous administration (r = 0.36, P < 0.01) and gestational age (r = 0.58, P < 0.01) were observed.In two of these in utero interventions, fetal urine was simultaneously collected. Fetal urine cefazolin concentrations were significantly higher than in AF. It is therefore to be anticipated that the GA-dependent increase in cefazolin concentration in AF in part reflects fetal renal maturation. The current observations on cefazolin disposition hereby illustrate the need to consider pharmacokinetic alterations during pregnancy as a continuous instead of a dichotomous variable.
Paediatric and Perinatal Drug Therapy 05/2008; 8(4):172-176.
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ABSTRACT: To document covariates which contribute to inter-individual variability in propofol pharmacokinetics in preterm and term neonates.
Population pharmacokinetics were estimated (non-linear mixed effect modelling) based on the arterial blood samples collected in (pre)term neonates after i.v. bolus administration of propofol (3 mg kg(-1), 10 s). Covariate analysis included postmenstrual age (PMA), postnatal age (PNA), gestational age, weight, and serum creatinine.
Two hundred and thirty-five arterial concentration-time points were collected in 25 neonates. Median weight was 2930 (range 680-4030) g, PMA 38 (27-43) weeks, and PNA 8 (1-25) days. In a three-compartment model, PMA was the most predictive covariate for clearance (P<0.001) when parameterized as [CL(std).(PMA/38)(11.5)]. Standardized propofol clearance (CL(std)) at 38 weeks PMA was 0.029 litre min(-1). The addition of a fixed value in neonates with a PNA of >/=10 days further improved the model (P<0.001) and resulted in the equation [CL(std).(PMA/38)(11.5) +0.03] for neonates >/=10 days. Values for central volume (1.32 litre), peripheral volume 1 (15.4 litre), and peripheral volume 2 (1.29 litre) were not significantly influenced by any of the covariates (P>0.001).
PMA and PNA contribute to the inter-individual variability of propofol clearance with very fast maturation of clearance in neonatal life. This implicates that preterm neonates and neonates in the first week of postnatal life are at an increased risk for accumulation during either intermittent bolus or continuous administration of propofol.
BJA British Journal of Anaesthesia 12/2007; 99(6):864-70. · 4.24 Impact Factor
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ABSTRACT: In addition to size-dependent allometric metabolic activity, most isoenzymes display age-dependent isoenzyme-specific ontogeny. We therefore need probe drugs to describe isoenzyme-specific ontogeny to develop more sophisticated, physiologically based models. We illustrate the feasibility and the relevance of in vivo assessment of hepatic metabolism, based on observations on urinary elimination of paracetamol and tramadol metabolites in neonates. On the basis of the observations on tramadol disposition, we were able to document that O-demethylation phenotypic activity developed sooner when compared with N-demethylation. During repeated administration of intravenous paracetamol, it was documented that, in addition to postmenstrual and postnatal age (PNA), repeated administration also contributed to the urinary excretion of glucuronidated paracetamol. In both probe drugs evaluated, age only in part explained the interindividual variability observed. Urine metabolites to assess in vivo metabolism of drugs routinely administered in neonates likely increase both the feasibility and clinical relevance of studies on in vivo isoenzyme-specific ontogeny in neonates.
Methods and Findings in Experimental and Clinical Pharmacology 06/2007; 29(4):251-6. · 0.93 Impact Factor
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European Journal of Anaesthesiology 05/2007; 24:117. · 2.23 Impact Factor
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ABSTRACT: A simple, accurate and fast method was developed for determination of the commonly used HIV protease inhibitors (PIs) amprenavir, indinavir, atazanavir, ritonavir, lopinavir, nelfinavir, M8-nelfinavir metabolite and saquinavir in human plasma. Liquid-liquid extraction was used with hexane/ethylacetate from buffered plasma samples with a borate buffer pH 9.0. Isocratic chromatographic separation of all components was performed on an Allsphere hexyl HPLC column with combined UV and fluorescence detection. Calibration curves were constructed in the range of 0.025-10 mg/l. Accuracy and precision of the standards were all below 15% and the lowest limit of quantitation was 0.025 mg/l. Stability of quality control samples at different temperature conditions was found to be below 20% of nominal values. The advantages of this method are: (1) inclusion and determination of the newly approved atazanavir, (2) simultaneous isocratic HPLC separation of all compounds and (3) increased specificity and sensitivity for amprenavir by using fluorescence detection. This method can be used for therapeutic drug monitoring of all PIs currently commercialised and is now part of current clinical practice.
Journal of Chromatography B 02/2007; 845(1):51-60. · 2.89 Impact Factor
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ABSTRACT: To document maturational changes of the in vivo activity of CYP3A4 in the first months of life.
The contribution of tramadol (M), O-demethyl tramadol (M1, CYP2D6-mediated) and N-demethyl tramadol (M2, CYP3A4-mediated) to the overall elimination of tramadol and the log M/M2 was assessed in 24-hour urine collections during continuous intravenous tramadol administration. Correlations with perinatal characteristics (postnatal age (PNA) and postmenstrual age (PMA)) were studied.
Of the total amount of tramadol administered in a 24-hour interval to 25 neonates and young infants (PMA 25 - 53 weeks), 34.5% (SD 6.1) were retrieved in the urine as parent compound or metabolite in a 24-hour interval. This retrieved material consisted primarily of tramadol 79% (SD 18), M1 10% (SD 17) and M2 3% (SD 3.4). The contribution of M (r2 = -0.53), M1 (r2 = 0.46) and M2 (r2 = 0.16) to overall M elimination correlated with increasing PMA. The mean log M/M2 was 1.44 (SD 0.46) and there was an inverse correlation between the log M/M2 ratio and PMA (r2 = -0.43, 95% CI for r = -0.84 to -0.34, p = 0.0006) and PNA (r2 = -0.25, 95% CI for r = -0.78 to -0.16, p = 0.008). The maturational half-life of the log M/M2 ratio was 16 - 20 weeks. In a multiple regression model, PMA was the only significant variable accounting for the interindividual variability in log M/M2.
PMA was found to be the most important maturational change determing the in vivo activity of CYP3A4. The activity of CYP3A4 is relatively delayed in the first months of life compared to the developmental changes in CYP2D6 activity described earlier, however, the overall weak correlations reflect that PMA explains only in part the interindividual variability observed.
International journal of clinical pharmacology and therapeutics 08/2006; 44(7):303-8. · 1.18 Impact Factor
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Basic & Clinical Pharmacology & Toxicology 02/2006; 98(1):110-2. · 2.18 Impact Factor
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ABSTRACT: Assess in vivo O-demethylation activity in the first months of life.
Time-concentration profiles of tramadol (M) and O-demethyl tramadol (M1) in plasma and urine were simultaneously collected in the first 24 h of continuous intravenous tramadol administration in neonates and young infants. M and M1 were determined by high performance liquid chromatography. Correlations between perinatal characteristics [postnatal age (PNA), postmenstrual age (PMA)] and the contribution of metabolites (M, M1) to overall tramadol elimination and to the plasma and urine log M/M1 were calculated.
Plasma samples were available in 20/29 and complete 24-h urine collections were available in 25/29 neonates (25-53 weeks PMA). Mean plasma log M/M1 value (>4 h, n=86) was 0.8 (SD 0.4). A significant correlation between plasma log M/M1 and PMA (r=-0.73, P<0.0001) and PNA (r=-0.58, P<0.005) was observed. In a multiple regression model, only PMA remained an independent variable. Mean urine log M/M1 was 0.94 (SD 0.7). Significant correlations of the urine log M/M1 ratio with PMA (r=-0.73, P<0.0001) and PNA (r=-0.56, P=0.0035) were observed. In a multiple regression model with the urine log M/M1 ratio as dependent variable, only PMA remained an independent variable. The maturational half-life of the log M/M1 ratio in early neonatal life in the age range evaluated is about 12-16 weeks without plateau.
O-demethylation activity was already observed in early neonatal life. A significant correlation with PMA was documented, but PMA can only partially explain the observed variability in O-demethylation activity. Polymorphism therefore likely already contributes to the interindividual variability observed in neonates.
European Journal of Clinical Pharmacology 01/2006; 61(11):837-42. · 2.85 Impact Factor
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ABSTRACT: Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available.
A population pharmacokinetic analysis of tramadol and M1 time-concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time-concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity.
Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h(-1) [70 kg](-1)) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric '1/4 power' models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg](-1)) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance.
Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 microg litre(-1) is achieved after a bolus of tramadol hydrochloride 1 mg kg(-1) and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg(-1) h(-1) at 25 weeks PCA, 0.14 mg kg(-1) h(-1) at 30 weeks PCA, 0.17 mg kg(-1) h(-1) at 35 weeks PCA, 0.18 mg kg(-1) h(-1) at 40 weeks, 0.19 mg kg(-1) h(-1) at 50 weeks PCA to 1 yr, 0.18 mg kg(-1) h(-1) at 3 yr and 0.12 mg kg(-1) h(-1) in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established.
BJA British Journal of Anaesthesia 09/2005; 95(2):231-9. · 4.24 Impact Factor
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ABSTRACT: Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood-brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.
European Journal of Clinical Pharmacology 03/2005; 60(12):911-3. · 2.85 Impact Factor
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British Journal of Clinical Pharmacology 03/2004; 57(2):224-5. · 2.96 Impact Factor
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ABSTRACT: The authors examined the effect of the cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 days in a double-blind, randomized, balanced, two-period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11-day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120 hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC(0-infinity), AUC(0-24), and Cmax, the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median tmax was 0.5 hours for both treatments. The harmonic mean elimination half-life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (+/- 30.8) and 235.1 (+/- 39.1) micrograms/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment-related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin.
The Journal of Clinical Pharmacology 02/2001; 41(1):107-12. · 2.91 Impact Factor
