1 Theophylline metabolism was studied using seven human cytochrome P-450 isoforms (CYPs), namely CYPlAl, 1A2, 2A6, 2B6, 2D6, 2E1 and 3A4, and microsomal epoxide hydroxylase (EH), expressed in human B-lymphoblastoid cell lines. 2 At a high theophylline concentration of 10 mm four CYPs (lAl, 1A2, 2D6, 2E1) catalyzed the metabolism of theophylline. 3 Theophylline had the highest affinity (apparent Km range 0.2-1.0 mM) for the CYPIA subfamily and the kinetics of metabolic formation mediated by CYP1A2indicated substrate-inhibition (K1 range 9-16 mM). 4 CYP1A2 catalyzed the demethylation of theophylline as well as its hydroxylation, and was associated with the highest intrinsic clearance (1995 1 h-' per mol CYP) to 1,3-dimethyluric acid (DMU). Therefore, this isoform can be considered to be the most important enzyme involved in theophylline metabolism in vitro. 5 CYP2El was responsible for a relatively high intrinsic clearance by 8-hydroxylation (289 1 h-' per mol CYP). The apparent Km value of this reaction was about 15 mm, suggesting that CYP2E1 may be the low-affinity high-capacity isoform involved in theophylline metabolism. 6 The affinity of theophylline for CYPlAl was comparable with that of its homologue 1A2. When induced, the participation of CYPlAl in theophylline metabolism may be important. 7 CYP2D6 played only a minor role and CYP3A4 was not active in the in vitro metabolism of theophylline. 8 Our findings confirm the major role of CYP1A2 in theophylline metabolism and explain why in vivo the elimination kinetics of theophylline are non-linear and in vitro theophylline metabolism by human liver microsomes does not obey monophasic kinetics. 9 The data suggest also that not only tobacco smoking but also chronic alcohol intake may influence theophylline elimination in man as ethanol induces CYP2E1.Keywords theophylline metabolism CYP1A2 CYP2E1 in vitro cDNA expressed microsomes

Kinetics of the novel immunosuppressive cyclosporine were determined in four patients with terminal renal failure. After a short intravenous infusion (2.05 to 3.5 mg/kg in 4 hr), blood and plasma concentrations were measured (HPLC and radioimmunoassay [RIA] up to 36 hr. After infusion, concentration curves of the drug were characterized by a rapid initial fall (t 1/2 alpha 0.10 +/- 0.03 hr), followed by a biphasic elimination phase with corresponding t 1/2s of 1.08 +/- 0.25 hr (t 1/2 beta) and 15.8 +/- 8.4 hr (t 1/2 gamma). The volumes of distribution, calculated from whole blood concentrations (HPLC), were 0.140 +/- 0.48 l/kg (volume of the central compartment) and 3.49 +/- 2.65 l/kg (volume of distribution at steady state), whereas systemic clearances were 0.369 +/- 0.08 l/hr/kg. Blood levels measured by RIA exceeded the HPLC values after the fourth hour by up to 100%, indicating the production of cross-reacting cyclosporine metabolites. Plasma concentrations were considerably lower than in whole blood. Elimination of unchanged cyclosporine in patients with renal failure appears to be of the same order as in those with normal kidney function. Modification of the initial dosage regimens is therefore probably not required.

The findings of this study indicate that i) microsomes from transfected human B-lymphoblastoid cell lines give results close to those obtained with microsomes isolated from human liver, ii) at least four CYP isoforms are involved in caffeine metabolism, iii) at a substrate concentration <0.1 mmol center dot l-1, CYP1A2 and 1A1 are the most important isoenzymes, iv) at higher concentrations the participation of other isoenzymes, in particular CYP3A4, 2E1 and possibly also CYP2D6-Met, are important in caffeine metabolism, and v) the nucleotide composition at position 1120 of CYP2D6 determines the activity of this isoenzyme in caffeine metabolism.

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The actual survival rate of 25 primary cadaveric kidney grafts in recipients treated initially with cyclosporin A (CyA) alone was 84%. The survival rate in 37 patients under conventional immunosuppression was 76%. The mean number of dialyses required in the first 4 weeks after transplantation was 1.2 per patient in both groups. At 15-28 months posttransplant, mean serum creatinine levels have remained stable at 175 mumol/l in the CyA group. The mean daily dose of steroids (including methylprednisolone i.v.) in the first two months was 2.07 mg/kg/d in patients under conventional immunosuppression and 0.76 mg/kg/d in the patients receiving CyA (p less than 0.001). The combination of CyA with low-dose steroids enabled the dose of CyA to be rapidly tapered off in once-weekly steps. CyA levels were monitored by determination of whole blood trough concentrations (target level: 300-800 ng/ml). At 60 days posttransplant the average dose of CyA was 6.0 +/- 0.5 mg/kg/d compared with an average daily dose of 11.4 +/- 0.9 as recommended for CyA alone in the protocol for the European multicentre study. This more rapid reduction in the CyA dose reduced nephrotoxicity (serum creatinine levels 174 +/- 14 as compared with 289 +/- 31 mumol/l) (p less than 0.05) and almost halved the number of methylprednisolone pulses given up to the end of the second month. We conclude from these results (1) that previously the dosage of CyA administered at this centre was probably too high, and (2) early adjustment of dose levels on the basis of blood concentrations and with low-dose prednisone cover appears to be safe and effective, but requires further verification.