Joseph J. H. M. Lohman

Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy.

Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (± 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284–452) and 2837 (CI95% 2101–3573) pmol/8 × 108 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7–92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.

Effect of heparin on digitoxin protein binding

Reduction of digitoxin binding to plasma proteins after heparin has been reported. Our aim was to determine whether this reduction is an in vivo effect or occurs only after blood collection as a result of heparin‐induced lipolysis that increases levels of nonesterified fatty acids in vitro. The effect of heparin on digitoxin protein binding was studied in 10 patients undergoing hemodialysis receiving digitoxin maintenance therapy. Digitoxin free fraction increased after heparin, from 2.5% ± 0.7% to 4.4% ± 1.1%, but after inhibition of in vitro lipolysis with diethyl p‐nitrophenyl phosphate (2mM), a potent lipase inhibitor, there was no increase in the free fraction (2.3% ± 0.4% before heparin and 2.4% ± 0.5% after heparin). Digitoxin salivary levels were also unchanged (0.41 ± 0.08 ng/ml before heparin and 0.41 ± 0.08 ng/ml after heparin [n = 8]). These data indicate that the binding of digitoxin to plasma proteins in vivo is not altered by heparin. The reduced binding reported elsewhere was a result of heparin‐induced in vitro lipolysis.

Do evacuated blood collection tubes interfere with therapeutic drug monitoring

The influence of various brands of evacuated blood collection systems (the old type, red stoppered Vacutainer®; the new type, blue stoppered Vacutainer®; Monoject® and Venoject®) on therapeutic drug monitoring was investigated. No interferences were found in the assay of ethosuximide, phenobarbital, phenytoin, valproic acid, digitoxin, digoxin, procainamide, gentamicin and theophylline.Using Monoject® and old type Vacutainer® tubes, lower levels were found in the disopyramide assay: 91.3±4.6% (p<0.05) and 91.7±7.0% (not significant) respectively, and in the quinidine assay: 82.8±6.7% (p<0.02) and 83.9±4.4% (p<0.001) respectively as compared with glass tubes. In the carbamazepine assay a decrease was found in the Monoject® tubes only: 93.7±1.7% (p<0.01). The stoppers of Monoject® tubes and the old type Vacutainer® tubes contained the plasticizer tris(2-butoxyethyl)phosphate (tbep), which has been shown to be a potent inhibitor of the binding of several drugs to α1-acid glycoprotein.Using the new type Vacutainer® and the Venoject®, no interferences were found.

Plasma protein binding of digitoxin and some other drugs in renal disease

Plasma protein binding of most acidic drugs is decreased in uraemia, whereas the binding of basic drugs is usually unchanged or decreased. Decreased protein binding in patients with renal disease mainly relates to drugs binding to albumin. Digitoxin binds to a specific site on the albumin molecule. Conflicting reports exist on digitoxin-protein binding in patients with renal disease. In ten patients with end-stage renal disease treated with haemodialysis we found only a slightly increased free fraction of digitoxin. A heparin-induced increase of the free fraction of digitoxin during haemodialysis has been reported. However, this increase was caused by the generation of non-esterified fatty acidsin vitro. If thisin vitro lipolysis was blocked, no increase of free digitoxin could be detected. Alterations of digitoxin-protein binding in uraemic patients during haemodialysis and during the intervals between haemodialysis treatments are small.

Pitfalls in the determination of unbound carbamazepine concentrations in plasma.

The usefulness of three simple, commercially available ultrafiltration systems [Centriflo CF25 (A), Centriflo CF50A (B) and Ultrafree (C)] in determining concentrations of unbound carbamazepine in plasma was tested. The concentrations of carbamazepine measured in the first fractions of the ultrafiltrate were low, probably as a result of binding of the drug to the ultrafiltration system. The amount of this binding decreased in the order A > B > C. When using A and B, the first portion of ultrafiltrate obtained after centrifuging for 15 minutes must therefore be discarded. Using the Ultrafree filters this was not necessary. Plasma proteins were found to pass through the Ultrafree filter membrane when more than 0.7 ml ultrafiltrate was collected. Comparison of the ultrafiltration methods with equilibrium dialysis showed a good correlation: r=0.96 (A), r=0.97 (B) and r=0.98 (C). However, in the carbamazepine plasma concentration range 2.5–10.0 μg/ml, significantly lower free fractions were measured with the Centriflo cones. The free fractions measured were: 0.28–0.30 (equilibrium dialysis), 0.17–0.18 (A), 0.22–0.24 (B) and 0.29–0.30 (C). The time required to collect the ultrafiltrate was 30 minutes (A and B) and 2 hours (C).

Comparison of clonazepam sorption to polyvinyl chloride-coated and polyethylene-coated tubings.

The sorption of clonazepam to polyvinyl chloride tubing, polyethylene-coated tubing and to a polyethylene syringe was determined. Pumping of clonazepam (5 mg/48 ml) through the polyvinyl chloride tubing with flow rates of 2 ml/h and 4 ml/h resulted in a reduction of the clonazepam concentration to about 40% and 55% of the original strength after 0.6 h, respectively. This value was 55% at a flow rate of 2 ml/h and a clonazepam concentration of 10 mg/48 ml. The effluent clonazepam concentration increased gradually after an infusion period of 1 h. Sorption of clonazepam to the polyethylene syringe and to the tubing coated on the inside with polyethylene does not occur. The use of polyethylene-coated administration sets is recommended for intravenous administration of clonazepam.

Ofloxacin intravenous. Compatibility with other antibacterial agents.

The physical and chemical compatibility of ofloxacin (infusion solution 100 ml=200 mg) with amoxicillin, amoxicillin+clavulanic acid, flucloxacillin, tobramycin, gentamicin, clindamycin, vancomycin, ceftazidime and piperacillin was investigated. Upon admixture with flucloxacillin a precipitate formed between 7 and 24 hours. No other physical or chemical incompatibilities were observed with any of the other combinations. Ofloxacin may be safely combined with the tested antimicrobial drugs, except for flucloxacillin.