Thiopurine drugs in the treatment of childhood leukaemia: the influence of inherited thiopurine methyltransferase activity on drug metabolism and cytotoxicity

Aims The response to 6-mercaptopurine (6MP) is highly variable. Its antileukaemic effect can be related to drug derived 6-thioguanine nucleotides (TGNs). The inherited level of thiopurine methyltransferase (TPMT) activity may be a major factor in the clinical response to 6MP because TPMT forms methylmercaptopurine metabolites (MeMPs) at the expense of TGNs. The aim of this study was to explore the clinical importance of TPMT phenotype.
Methods Thiopurine metabolism was studied in a consecutive cohort of children with acute lymphoblastic leukaemia (ALL) treated according to the Medical Research Council trial UK ALL XI. TPMT phenotype was measured in 38 children at diagnosis, and thiopurine metabolites were measured at defined times during 2 years treatment in 29 of these children.
Results TPMT activities at diagnosis ranged from 5.5 to 18.5 units  ml⁻¹ packed RBCs, no different from the range of activities reported in healthy children. TGNs and MeMPs measured during the first 6MP cycle at 75  mg  m⁻² ranged from 187 to 594  pmol 6TGNs, median 327, and 0.5 to 22.0  nmol MeMPs, median 4.5, per 8×10⁸ RBCs. TPMT activity was not significantly related to the generation of MeMPs ( r _s=0.06), but was negatively correlated to 6TGNs ( r _s=−0.44, P <0.025, n =29). TGNs were related to neutropenia at the point of dose reduction ( r _s=−0.5, P <0.01). TPMT activity was also inversely related to the duration of cytopenia driven 6MP withdrawal ( r _s=−0.41, P <0.05).
Conclusions These findings support the suggestion that the inherited activity of TPMT in a given individual can modulate the cytotoxic effect of 6MP, and this information may help in clinical management.     

Faecal DNA and calprotectin as biomarkers of acute intestinal toxicity in patients undergoing pelvic radiotherapy

Background  Acute intestinal toxicity is a frequent complication that may lead to interruption of treatment in patients undergoing pelvic radiotherapy. Reliable, non-invasive biological markers to evidence their severity are not yet available.
Aim  To test faecal DNA and calprotectin as potential biomarkers of intestinal toxicity caused by pelvic radiotherapy.
Methods  Patients were categorized according to the location of the cancer as nonrectal ( n  = 25) and rectal ( n  = 27). Four stool samples were collected at weeks w0, w3, w5 (end of radiotherapy) and w7. Faecal DNA was determined by quantitative PCR and calprotectin by ELISA. Intestinal toxicity was scored according to the Common Toxicity Criteria.
Results  In the nonrectal group, acute diarrhoea toxicity was present in 80% of patients, faecal DNA increased 10-fold during radiotherapy (1.5 × 10³ copies/mg dry weight, 9.5 × 10²–8.8 × 10³ at w0, median and interquartile range vs. 1.3 × 10⁴, 1.9 × 10³–3.9 × 10⁴ at w5, P  < 0.01), but was not recovered at w7 (3.4 × 10³, 1.5 × 10³–4.1 × 10⁴) and calprotectin doubled during treatment at w3 and w5. No significant changes in faecal markers were found in the rectal group.
Conclusion  Faecal excretion of human DNA and calprotectin increased during pelvic radiotherapy treatment, and may be a good objective biomarker of intestinal damage in nonrectal cancer patients.     

Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application

Aims The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin-2 (rhIL-2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens.
Methods RhIL-2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20×10⁶  IU  m⁻² once daily and group B 10×10⁶ IU  m⁻² twice daily (every 12  h). Additionally, in all patients the influence of soluble interleukin-2 receptor (sIL-2R) on the pharmacokinetics of rhIL-2 was investigated.
Results The mean area under the serum concentration-time curve to 24  h (AUC(0,24  h)) was 627  IU  ml⁻¹  h in treatment group A and 1130  IU  ml⁻¹  h ( P =0.029) in treatment group B. In both study groups C _max and AUC(0,12  h) were not significantly different. Seventy-two  hours after the beginning of s.c. rhIL-2 therapy the sIL-2R increased significantly ( P =0.016), and sIL-2R levels over 1200  pmol  l⁻¹ seemed to reduce the AUC.
Conclusions In patients with metastatic renal cell cancer administration of 20×10⁶  IU  m⁻² of rhIL-2  s.c. in two daily doses (10×10⁶  IU  m⁻² every 12  h) provides better bioavailability and is preferable to the single dose administration.     

Effect of protease inhibitors on nucleoside analogue phosphorylation in vitro

Aims Combination antiretroviral therapy for human immunodeficiency virus (HIV) infection now involves both nucleoside analogues and protease inhibitors. Since intracellular phosphorylation is essential for the activity of all the nucleoside analogues this study was designed to investigate interactions with protease inhibitors at the intracellular level which may alter antiviral efficacy.
Methods PHA-stimulated PBMCs (3×10⁶ cell/plate) and U937 cells (4×10⁶ cells/plate) were incubated with either radiolabelled zidovudine (ZDV), stavudine (d4T), zalcitabine (ddC), lamivudine (3TC) or didanosine (ddI) in the presence and absence of the protease inhibitors, indinavir, ritonavir, and saquinavir (0.1−10  μm ) for 24  h. Cells were extracted overnight prior to analysis by radiometric h.p.l.c. Intracellular phosphates were standardised to  pmol per million cells.
Results None of the three protease inhibitors tested had any significant effect on the intracellular phosphorylation of the five nucleoside analogues. It is particularly important to focus on the active triphosphate anabolites and data for control vs ritonavir (10  μm ) incubations in U937 cells were as follows: ZDVTP, 0.19±0.02 vs 0.21±0.02  pmol/10⁶ cells (mean±s.d.; n =5); d4TTP, 0.30±0.13 vs 0.27±0.26; 3TCTP, 0.32±0.12 vs 0.26±0.19; ddCTP, 0.07±0.04 vs 0.06±0.02; ddATP, 0.014±0.003 vs 0.018±0.006  pmol/10⁶ cells.
Conclusions The protease inhibitors, indinavir, ritonavir and saquinavir have no effect on the enzymes responsible for phosphorylation. Combining protease inhibitors and nucleoside analogues should not lead to any intracellular interactions in vivo .     

Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer''s disease

Aims To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease.
Methods The pharmokinetics of a single 40  mg oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2  mg  kg⁻¹ [¹³C-3-methyl] caffeine orally and had breath and urine samples collected.
Results Tacrine oral clearance (CL   F ⁻¹  kg⁻¹ ), which varied 15-fold among the patients, correlated significantly with the 2  h total production of ¹³CO₂ in breath ( r =0.56, P =0.01), and with each of two commonly used urinary caffeine metabolite ratios: the raxanthine/caffeine ratio' (1,7X+1, 7U)/1,3,7X) ( r =0.76, P =0.0002) and the 'caffeine metabolic ratio' (AFMU+1X+1U)/1, 7U)( r =0.76, P =0.0001).
Conclusions These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme. The magnitude of the correlations we observed, however, are probably not suffcient to be clinically useful in individualizing tacrine therapy.     

A comparative population pharmacokinetic analysis for methylprednisolone following multiple dosing of two prodrugs in patients with acute asthma

Aims To conduct a randomized, parallel group comparison of the population pharmacokinetics of the two methylprednisolone (MP) prodrugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) in patients hospitalized with acute asthma.
Methods Ninety volunteers were included in the pharmacokinetic analysis. Each volunteer received a dosage regimen of 40  mg (MP equivalents) i.v. 6 hourly for 48  h. The bio-conversion and disposition of a 40  mg (MP equivalent) i.v. dose of either MP suleptanate or MP succinate to MP was modelled as a first order input, and a mono-exponential elimination phase.
Results Population modelling indicated that the only difference in MP pharmacokinetics between MP suleptanate and MP succinate was in the input rate constant (66.0  h⁻¹ vs 5.5  h⁻¹ respectively). Based on individual Bayesian estimates, the exposure of patients to MP was marginally lower for MP suleptanate although the parameter estimates were not significantly different for half-life (2.7  h vs 3.0  h), steady-state AUC (2007.0  ng  ml⁻¹  h vs 2321.0  ng  ml⁻¹  h) and steady-state C _max (698.4  ng  ml⁻¹ vs 647.8  ng  ml⁻¹ ) for MP suleptanate and MP succinate respectively.
Conclusions It was concluded that for the multiple dosage regimen used in patients with acute asthma the systemic exposure to MP following dosing with MP suleptanate is similar to that arising from MP succinate. In addition the differences in the pharmacokinetics for the prodrugs resulted in only a small difference in the relative bioavailability of MP for MP suleptanate (0.94) compared with MP succinate.     

Intra-arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability

Aims The current studies were designed to characterize the pharmacology, reproducibility and tolerability of the vasodilator response to intra-arterial substance P infusion in the forearm of healthy man.
Methods On different occasions, eight healthy male volunteers received brachial artery infusions of substance P at doubling doses ranging from 0.5 to 128  pmol min⁻¹. Blood flow was measured in both arms using venous occlusion plethysmography.
Results Substance P induced dose-dependent vasodilatation in the human forearm which had a log-linear relationship to dose. At doses of 1–8  pmol min⁻¹, mean responses were highly reproducible both within and between days. There were no differences between responses to discontinuous doses and continuous doses of substance P. Substance P was generally well tolerated at doses of ≤64  pmol min⁻¹ with no significant alteration in arterial blood pressure or heart rate. Skin oedema in the infused forearm and systemic vasodilatation, manifested by facial flushing and non-infused forearm vasodilatation, occurred at doses of ≥16  pmol min⁻¹.
Conclusions Forearm vasodilatation to substance P represents a reproducible and useful model in the assessment of peripheral endothelial cell NK₁ receptor function.     

Analysis of drug resistance and virulence‐factor genotype of Irish Helicobacter pylori strains: is there any relationship between resistance to metronidazole and cagA status?

Background  Helicobacter pylori infection is eradicated with antimicrobial agents and drug-resistant strains make successful treatment difficult. Geographical variations in virulence-factor genotype also exist.
Aim  To evaluate prevalence of drug resistance and virulence-factor genotype in Irish H. pylori strains and to investigate if there is any relationship between drug resistance and genotype.
Methods  Helicobacter pylori strains isolated from 103 patients were examined. Antimicrobial susceptibilities were tested by Etest. The virulence-factor genotypes were determined using PCR. Frequencies of spontaneous metronidazole-resistance were measured in vitro .
Results  Metronidazole resistance was present in 37.9% of strains examined. 16.5% of strains were clarithromycin-resistant and resistance to both agents observed was found in 12.6% of strains. 68% of strains were cagA ⁺. The dominant vacA type was s1/m2, followed by s1/m1 and s2/m2. The metronidazole resistance rate in cagA ⁻ group was significantly higher than in cagA ⁺ ( P  =   0.0089). Spontaneous resistance to metronidazole in cagA ⁻ occurred in higher frequency when compared with cagA ⁺.
Conclusions  cagA ⁺ and vacA s1/m2 type was the dominant genotype in Irish H. pylori strains. Significant rates of metronidazole resistance were observed in cagA ⁻ group. cagA ⁻ strains tend to acquire metronidazole resistance in vitro . Absence of cagA might be a risk factor in development of metronidazole resistance.     

Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

Aims Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2  h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Methods Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40  mg  kg⁻¹ were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70  kg person using an allometric power model.
Results Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2  l  h⁻¹ (CV 47%), volume of distribution 67.1  l (CV 58%) and absorption rate constant 0.77  h⁻¹ (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72  h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Conclusions Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2  h before anticipated pain or fever in children.     

Constant rate infusion of vancomycin in premature neonates: a new dosage schedule

Aims Since vancomycin's bactericidal action has been shown to be time-dependent, a constant rate infusion over 24  h might result in a better bactericidal efficacy. The purpose of this study was to define a new dosage schedule in prematures.
Methods Two vancomycin 24  h constant rate infusion schedules were tested in two groups of neonates. Postconceptional age (PCA) was 27 to 41 weeks in group 1 ( n =24) and 28 to 51.5 weeks in group 2 ( n =29). Group 1 neonates received continuous infusion of 10 to 30  mg  kg⁻¹ day⁻¹, adjusted for PCA and weight. Group 2 was designed to take into account the significant relationship observed in group 1 between vancomycin clearance standardized on weight and PCA and consisted of a constant loading dose of 7  mg  kg⁻¹ followed by continuous infusion of 10 to 40  mg  kg⁻¹ day⁻¹ adjusted for PCA and weight.
Results Mean vancomycin serum concentration at steady state was 11±3.1  mg  l⁻¹ in group 1 and 15.4±6.2  mg  l⁻¹ in group 2. Fifty-six percent of group 1 values vs 88% of group 2 values were between 10 and 30  mg  l⁻¹ at steady state ( P <0.01). Both regimens were well tolerated.
Conclusion A loading dose of vancomycin followed by constant rate infusion of the appropriate dose adjusted for PCA and weight might improve vancomycin concentrations in neonates.     

The effects of ziprasidone on steady‐state lithium levels and renal clearance of lithium

Aims   To assess the potential of ziprasidone to alter the renal clearance and steady‐state serum levels of lithium.
Methods  Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day^{− 1}, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day^{− 1}, given as two divided daily doses, on days 9–11 followed by 80 mg day^{− 1}, given as two divided daily doses on days 12–15 ( n  = 12), or placebo twice daily ( n  = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium.
Results   Ziprasidone administration was associated with a 0.07 mmol l^{− 1} (13%) mean increase in steady‐state serum lithium levels compared with a mean increase of 0.06 mmol l^{− 1} (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h^{− 1} (5%) in the ziprasidone group and by 0.14 l h^{− 1} (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant.
Conclusions   Ziprasidone does not alter steady‐state serum lithium concentrations or renal clearance of lithium.     

Atovaquone has no effect on the pharmacokinetics of phenytoin in healthy male volunteers

The potential pharmacokinetic interaction between atovaquone and phenytoin was investigated in 12 healthy male volunteers. Each volunteer received a single 600  mg oral dose of phenytoin in the two treatment periods. On one occasion phenytoin was taken alone and on the other after pre-treatment with 2000  mg atovaquone taken as two doses of 1000  mg as a microfluidized suspension. The mean (±s.d.) peak plasma concentrations ( C _max), apparent total clearance (CL/ F ) and terminal half-life ( t _½) for phenytoin when administered alone were 10.6(1.8)  mg l⁻¹, 24.3 (7.7)  ml min⁻¹ and 25(8)  h, respectively. When administered together with atovaquone, phenytoin C _max, CL/ F and t _½,z were 10.9 (2.0)  mg l⁻¹, 23.8  ml min⁻¹ and 24(6)  h, respectively. There were no statistically significant differences in any of these plasma pharmacokinetic parameters. There were also no statistically significant differences in the fraction of circulating drug not bound to plasma protein or urinary excretion of 5-hydroxyphenyl-phenyl-hydantoin. In conclusion, there was no effect of atovaquone on the pharmacokinetics of phenytoin or its major metabolite after a single dose.     

The airway effects of stopping regular oral theophylline in patients with asthma

Aims We investigated whether the deterioration in asthma control reported following cessation of theophylline was due to tolerance to theophylline.
Methods Eighteen subjects with mild stable asthma were given oral theophylline 10  mg  kg⁻¹ day⁻¹ or placebo for 2 weeks in a double-blind crossover study. FEV₁ and PD₂₀ histamine were measured before and 8  h after the first dose of treatment and 8, 32 and 56  h after the final dose. PD₂₀ AMP was measured before treatment and 9  h after the final dose.
Results Six patients did not tolerate theophylline. In the other 12 subjects there were no differences between treatments in daily PEF, symptom scores, rescue bronchodilator use, PD₂₀ histamine or FEV₁ up to 8  h post treatment. Following withdrawal of theophylline there were significantly lower values for mean FEV₁ (mean difference 0.15  l, 95% CI 0.03, 026) and PD₂₀ AMP compared to placebo but no difference in other end points.
Conclusions The small rebound deterioration in lung function following regular treatment with therapeutic doses of oral theophylline is consistent with the development of tolerance.     

Methadone distribution and excretion into breast milk of clients in a methadone maintenance programme

Aims Methadone is widely used in maintenance programs for opioid-dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug.
Methods Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20–80  mg (0.3–1.14  mg  kg⁻¹ ). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms.
Results The mean (95% CI) milk/plasma ratio was 0.44 (0.24–0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15  l  kg⁻¹  day⁻¹ and a bioavailability of 100% was 17.4 (10.8–24)  μg  kg⁻¹  day⁻¹. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07–3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5  μg  l⁻¹ . Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen.
Conclusions We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.     

Erythropoietin production in healthy volunteers subjected to controlled haemorrhage: evidence against a major role for adenosine

1 This study was carried out to assess the role of adenosine in the regulation of human erythropoietin (EPO) production. To this end we investigated in healthy volunteers whether the nonspecific adenosine antagonist theophylline increases and the adenosine uptake inhibitor dipyridamole decreases EPO production in response to an haemorrhage of 750  ml.
2 Healthy male nonsmokers received i.v. in a parallel, randomized, single-blind trial theophylline (loading dose 5  mg  kg⁻¹ over 20  min, followed by 0.5  mg  kg⁻¹ min⁻¹), dipyridamole (0.21  mg  kg⁻¹ h⁻¹) or placebo (0.9% NaCl) for 6  h following the phlebotomy. EPO concentrations were followed up to 72  h after phlebotomy.
3 Following blood loss EPO concentrations increased during all treatments. The AUC_EPO (0,72  h) were not statistically significantly different (theophylline: 398±30, dipyridamole: 301±15, placebo: 332±57 [mu  ml⁻¹ h]). Creatinine clearance and urinary cAMP excretion were unaltered by any treatment. Urinary excretion of adenosine was significantly increased during infusion of dipyridamole. Plasma renin activitiy was significantly increased during theophylline infusion.
4 In our model of controlled, physiological stimulation of EPO production by haemorrhage, adenosine appears unlikely to play a major role as a mediator of renal EPO production.     

Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function

1 The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function.
2 After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0±3.0, 11.1 ± 3.0, 8.7 ± 3.7 and 6.7 ± 2.1 l h^-1 (means ± s.d.) in patients with creatinine clearances (CL_cr) of > 100, 41-100, 21-40, and 8-20 ml min^-1, respectively.
3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CL_cr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CL_cr < 40ml min^-1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups.
4 This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.     

Distribution and excretion of venlafaxine and O-desmethylvenlafaxine in human milk

Aims To characterise the transfer of venlafaxine (V) and its O -desmethyl metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to estimate the likely dose received by a breast-fed infant.
Methods Milk and plasma samples were collected from three lactating women who were taking venlafaxine for depression, and were at steady-state. In two of the patients, venous blood and milk samples were collected 0, 1, 2, 3, 4, 6, 8 and 12  h post dose, while in the third patient a single pair of blood and milk samples was obtained 0.83  h post dose. A plasma sample was obtained from each of their infants. V and ODV were measured in plasma and milk by high performance liquid chromatography. M/P was calculated and infant dose estimated as drug concentration in milk×a milk intake of 0.15  l  kg⁻¹  day⁻¹ , relative to the weight-adjusted maternal dose.
Results Mean M/P for V was 4.1 (range 2.8–4.8) and 3.1 for ODV (range 2.8–3.8). The mean total infant dose (as V equivalents) was 7.6% (range 4.7–9.2%) of the maternal weight-adjusted dose, with approximately equal amounts of V (3.5%) and ODV (4.1%) in the dose. ODV (median 100  μg  l⁻¹ ) was detected in the plasma of all three infants. The infants were healthy and showed no acute adverse effects.
Conclusions These preliminary data show that the total dose of V and ODV ingested by breast-fed infants can be as high as 9.2% of maternal intake. Moreover there were measurable concentrations of ODV in the infants' plasma. We recommend that exposed infants should be observed closely.     

Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

1 To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500  mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine.
2 Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0±7.8 vs 53.7±14.3  h, means±s.d., P< 0.001) and higher apparent oral clearance (CL/ F) values (15.3±3.8 vs 9.2±1.9  ml  kg⁻¹  h⁻¹, P< 0.001). The apparent volume of distribution ( V/F) of ethosuximide was slighty lower in the patients than in controls (0.6±0.1 vs 0.7±0.1  l  kg⁻¹, P< 0.05).
3 These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity.
4 The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.     

Relationships among liver and kidney volumes, lean body mass and drug clearance

Aims To determine whether lean body mass (LBM), a possible surrogate of liver and kidney volumes, correlates with hepatic and renal drug clearances.
Methods Twenty-one disease-free patients with a history of cancer and with normal hepatic and renal function were studied. Salivary pharmacokinetics of oral antipyrine (1200  mg) and 24  h creatinine clearance were determined following the determination of LBM by dual energy X-ray absorptiometry and the determination of liver and kidney volumes by helical CT scanning.
Results Liver volume correlated with LBM ( r ²=0.21, P =0.04), body surface area (BSA) ( r ²=0.54, P <0.001), and total body weight (TBW) ( r ²=0.61, P <0.001). Kidney volume correlated with LBM ( r ²=0.49, P <0.001), BSA ( r ²=0.43, P =0.002) and TBW ( r ²=0.24, P =0.03). Stepwise multiple regression analysis, incorporating the independent variables of age, height, weight, sex, BSA, LBM, alcohol consumption, smoking status and liver volume and the dependent variable antipyrine clearance, indicated that LBM was the only independent correlate of antipyrine clearance. A stepwise multiple regression analysis with kidney volume in the independent variables, and creatinine clearance as dependent variable, showed that kidney volume and age were the only independent correlates of creatinine clearance. A nomogram using serum creatinine and LBM was comparable with the Cockcroft and Gault nomogram in calculating creatinine clearance.
Conclusions Of the anthropometric variables tested, LBM was the only determinant of antipyrine clearance, but this was not due to a relationship between LBM and liver volume. By contrast, the relationship between creatinine clearance and LBM appeared to be due to a relationship between LBM and kidney volume.     

Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis

Aims Neoral is a new microemulsion form of cyclosporin. Pharmacokinetic reports in children are scarce. Therefore, we performed a pharmacokinetic study between Cyclosporin A (CsA) capsules and Neoral in paediatric patients with lupus nephritis.
Methods A single 5  mg  kg⁻¹ dose orally of either CsA capsules or Neoral was given to 10 paediatric patients (serum creatinine<1.5  mg dl⁻¹ ). CsA whole blood levels were measured for 24  h post-dose by h.p.l.c.
Results Neoral had a higher C _max and AUC( C _max: 943±176  ng  ml⁻¹; AUC: 4612±785  ng  ml⁻¹  h) than those of the CsA capsules ( C _max: 697±187  ng  ml⁻¹; AUC: 3483±873  ng  ml⁻¹  h; P <0.05). There was no difference in t _max and t _1/2,z between the two groups.
Conclusions CsA Neoral had improved absorption and bioavailability, which is similar to what is reported in adults. However, interpatient variability still existed. Careful drug monitoring and dose adjustment should be performed during treatment to avoid nephrotoxicity, especially in lupus nephritis.