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Intramuscular injection of diclofenac is still frequently practiced, although there is ample evidence that the risk of local tissue intolerability is highly underestimated. The aim of this study was to evaluate local toxicity in a patient using magnetic resonance imaging. A patient who gave written informed consent received a medically indicated intramuscular administration of diclofenac 75 mg/2 mL. Simultaneously with magnetic resonance imaging of the depot, a clinical–chemical evaluation and quantification of diclofenac in plasma was performed. A manifold enhancement of the T2-weighted magnetic resonance signal was observed in a muscle area of approximately 60 mL volume, with maximum signal intensity 30 min after injection, the time of maximum diclofenac plasma exposure. Plasma creatine kinase activity was elevated approximately sixfold within 8 h and normalized within 1 week, whereas the magnetic resonance enhancement disappeared within 5 weeks. Interestingly, the patient did not complain about any clinical symptoms at the injection site. Asymptomatic tissue injury after intramuscular injection of diclofenac, caused by intramuscular dosing, can be reliably evaluated by magnetic resonance imaging and should be applied early during the development of parenteral dosage forms. Clinical Trials Registration Number: BB130/16 (Ethics Committee of the University Medicine Greifswald).

Abstract

Background and methods: The antiepileptic drug carbamazepine is known to be an inducer of cytochrome P450 (CYP) 3A4 after binding to the nuclear pregnane X receptor. To evaluate whether it also regulates the multidrug transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein MRP2 in humans, duodenal expression of multidrug resistance gene MDR1 messenger ribonucleic acid (mRNA) and MRP2 mRNA, content of P-gp and MRP2, and disposition of the nonmetabolized P-gp substrate talinolol after intravenous (30 mg) and long-term oral administration (100 mg for 19 days) were assessed in 7 healthy subjects (age, 23-35 years; body weight, 64-93 kg) before and after comedication of carbamazepine (600 mg for 14-18 days).Results: Carbamazepine medication was associated with increased urinary excretion of D-glucaric acid and induction of carbamazepine elimination. Creatinine clearance was not affected. Duodenal expression of both MDR1 mRNA and MRP2 mRNA and the MPR2 protein was significantly induced, whereas the P-gp content was not affected. MDR1 mRNA expression and MPR2 mRNA expression were correlated (r = 0.873, P < .001). After carbamazepine, metabolic clearance of intravenous talinolol was significantly increased. Residual clearance was significantly decreased in dependence on MDR1 mRNA expression (r = −0.647, P = .012) and MRP2 mRNA expression (r = −0.613, P = .020). Oral absorption of talinolol was significantly lower after carbamazepine comedication (53.2% ± 15.5% versus 62.1% ± 13.0%, P = .018), and renal clearance and metabolic clearance were significantly increased, correlated in each case with MDR1 mRNA (r = 0.612, P = .020, and r = 0.554, P = .040, respectively) and MRP2 mRNA (r = 0.596, P = .025, and r = 0.565, P = .035, respectively).Conclusions: Aside from induction of CYP3A4, carbamazepine acts as an inducer of intestinal MDR1 mRNA, MRP2 mRNA, and MRP2 protein content.Clinical Pharmacology & Therapeutics (2004) 76, 192–200; doi: 10.1016/j.clpt.2004.04.011

Background: Clinical trials have indicated that the combined β- and α-adrenergic receptor blocker carvedilol improves the survival rate in patients with advanced chronic heart failure. The objective of our study was the identification and quantification of factors that modulate steady-state serum concentrations of carvedilol and its enantiomers and that may influence therapeutic efficacy and safety.Methods: The influence of genetic variants of cytochrome P450 (CYP) 2D6 and CYP2C9 and of transporter proteins (P-glycoprotein, multidrug resistance protein 2 [MRP2]) on the disposition of carvedilol and its enantiomers after intravenous (5 mg) and long-term oral administration (25 mg for 7 days) was assessed in 12 healthy subjects. The intestinal expression of P-glycoprotein and MRP2 was analyzed by quantitative real-time polymerase chain reaction and immunohistochemical techniques.Results: The area under the serum concentration–time curve (AUC) values of carvedilol were significantly (P < .05) increased in 6 subjects with CYP2D6 deficiency, with effects being more pronounced for R(+)-carvedilol (230 ± 72.6 ng · h/mL versus 93.9 ± 64.6 ng · h/mL in extensive metabolizers) than for S(−)-carvedilol (62.9 ± 21.1 ng · h/mL versus 32.7 ± 14.5 ng · h/mL). The AUC and fecal excretion of intravenous carvedilol were correlated with the intestinal expression of MDR1 messenger ribonucleic acid (mRNA) (r = −0.67, P = .001; r = 0.83, P = .002) and MRP2 mRNA (r = −0.74, P < .001; r = 0.70, P = .025). Furthermore, we measured the disposition of long-term oral carvedilol after comedication of the pregnane X receptor ligand rifampin (INN, rifampicin) (600 mg, 9 days), which up-regulates both P-glycoprotein and MRP2 but not CYP2D6. Rifampin decreased the AUC of carvedilol to an extent independent of the CYP2D6 genotype (poor metabolizers, 341 ± 147 ng · h/mL versus 126 ± 41.7 ng · h/mL; extensive metabolizers, 173 ± 102 ng · h/mL versus 74 ± 41.4 ng · h/mL; both P < .05). The AUC was significantly correlated with intestinal expression of MDR1 mRNA (r = −0.671, P = .001) and MRP2 mRNA (r = −0.595, P < .006).Conclusions: Variable plasma concentrations of carvedilol during long-term administration are predicted by CYP2D6 genotype and intestinal expression of P-glycoprotein and MRP2.Clinical Pharmacology & Therapeutics (2004) 75, 213–222; doi: 10.1016/j.clpt.2003.10.004