Polymorphic oxidation has been described for debrisoquine (Mahgoub et al. 1977) and for sparteine (Eichelbaum et al. 1979). Reduced ability to oxidize these compounds is inherited as an autosomal recessive trait (Price-Evans et al. 1980), and the prevalence of the slow hydroxylator phenotype varies between 3% and 9%, depending on the country (Eichelbaum 1982). Biochemical studies indicate that this polymorphism is caused by an inherited absence or functional deficiency of a particular cytochrome P-450 isozyme, called debrisoquine hydroxylase (Boobies et al. 1983). The oxidative metabolism of several other drugs has been shown to cosegregate with the debrisoquine/sparteine oxidation polymorphism (Jacqz et al. 1986).

Bertilsson, Leif; Åberg-Wistedt, Anna*; Dumont, Etienne; Lundström, Jan† Author Information

Conjugation of racemic E-10-hydroxynortriptyline (E-10-OH-NT) with glucuronic acid was studied in the liver microsomal fraction of rats and humans. The diastereomeric glucuronides of E-10-OH-NT were resolved and quantitated by HPLC. Only the (+)-enantiomer was glucuronidated in liver microsomes from humans. Rat liver microsomes catalyzed the formation of both glucuronides. Phenobarbital pretreatment of rats increased the glucuronidation of both enantiomers about five-fold. The formation rate of (+)-E-10-OH-NT glucuronide varied from 5.5 to 33.2 pmol/mg x min, in microsomes from 13 humans. High activity was found in individuals previously treated with pentobarbital. Inhibition experiments with human liver microsomes showed that amitriptyline is a potent competitive inhibitor of (+)-E-10-OH-NT glucuronidation. p-Nitrophenol, paracetamol and 2-hydroxydesipramine also inhibited this reaction.

The plasma kinetics of mitoxantrone (MX), a new cytostatic anthracenedione, were investigated with HPLC in five leukemic patients suffering from acute myeloid leukemia, at the dose of 24 mg m−2 infused over 30 min at constant rate. The decay of the plasma concentrations was best fitted to a three compartment model with average elimination half-lives of respectively 4.1 min (α-phase), 19.8 min (β-phase) and 8.9 h (γ-phase), a mean distribution volume of 317 l m−2 and an average total body clearance of 0.37 l min−1 m−2. The cumulative urinary recovery of unchanged MX was 7.5% of the administered dose in 4 days, with the highest elimination during the first day. No MX urinary metabolites or conjugates have been detected.

The acute effects of a single i.v. bolus injection of mitoxantrone (MX), a cytostatic drug, on mean arterial pressure (MAP), left ventricular pressure (LVP), dp/dtmax and ECG, were investigated at different doses (1,2,3,5 and 10 mg/kg) in conscious rabbits. Low values of MAP, LVP and dp/dtmax and increased heart rate were observed at 2 h after injection at all dose levels exceeding 1 mg/kg. Plasma kinetics and urinary elimination of MX were determined by high-pressure liquid chromatography (HPLC) and appraised at two dose levels (1.5 mg/kg and 3 mg/kg). MX plasma decay curve at both doses could be fitted to a curve with three exponential components, with an average elimination (3rd component) half-life of about 3.5 h (1.5 mg/kg) and about 5 h (3 mg/kg), respectively. Renal failure was observed in 3 mg/kg-dosed rabbits (elevation of BUN and plasma creatinine, anuria), and resulted in a considerable delay in the MX plasma decay and in a depressed urinary elimination of MX. All but one rabbit died within 24 h. The 1.5 mg/kg-dosed rabbits survived till 24 h, without signs of renal failure, with a 24 h urinary MX recovery of 20%.