Biomedical subjects
Roberto Padrini
Publications and source records attributed to Roberto Padrini.
Effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function.
AIMS: The objectives of this study were: (i) to evaluate the effect of a cytochrome P450 (CYP) 3A4 inhibitor, erythromycin, on the pharmacokinetics of intravenous lignocaine and its two pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX); (ii) to assess whether the effects of the erythromycin inhibitory action on lignocaine clearance and the results of the MEGX liver function test depend on liver functional status; and (iii) to determine the effects of both moderate and severe liver dysfunction on the disposition kinetics of lignocaine. METHODS: The study was carried out on 10 healthy volunteers, and 10 Child's class A and 10 class C cirrhotic patients, according to a double-blind, randomized, two-way crossover design. On day 1 of the investigation, all subjects received three oral doses of erythromycin (600 mg of the ethylsuccinate ester) or placebo, and two further doses on day 2. One hour after the fourth dose, subjects were given 1 mg kg-1 lignocaine intravenously. Timed plasma samples were then obtained until 12 h for determination of the concentrations of lignocaine, MEGX and GX. RESULTS: Erythromycin caused statistically significant, although limited, modifications of lignocaine and MEGX pharmacokinetic parameters. In healthy volunteers, lignocaine clearance was decreased from 9.93 to 8.15 ml kg-1 min-1[mean percentage ratio (95% CI), 82 (65-98)] and the half-life was prolonged from 2.23 to 02.80 h [mean percentage ratio (95% CI), 130 (109-151)]; MEGX area under the concentration-time curve from 0 h to 12 h was increased from 665 to 886 ng ml-1 h [mean percentage ratio (95% CI), 129 (102-156)]. Quantitatively similar modifications were observed in the two cirrhotic groups. GX concentrations were lowered in all study groups, although not to statistically significant extents. Erythromycin coadministration caused no appreciable interference with the results of the MEGX test. Only in patients with Child's grade C liver cirrhosis were lignocaine kinetic parameters significantly altered with respect to healthy volunteers. Thus, clearance was approximately halved, steady-state volume of distribution was increased, and terminal half-life was more than doubled. CONCLUSIONS: Although erythromycin only modestly decreases lignocaine clearance, it causes a concomitant elevation of the concentrations of its pharmacologically active metabolite MEGX. A pharmacodynamic study following lignocaine infusion to steady state appears necessary to assess the actual clinical relevance of these combined effects. The degree of liver dysfunction has no influence on the extent of the erythromycin-lignocaine interaction, whereas it markedly influences the extent of the changes in lignocaine pharmacokinetics. These findings indicate that no dose adjustment is needed in patients with moderate liver cirrhosis, whereas the lignocaine dose should be halved in patients with severe cirrhosis.
Reduced von Willebrand factor survival in type Vicenza von Willebrand disease.
Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype.
Relationships between body composition parameters and fluorouracil pharmacokinetics.
AIMS: To verify whether fluorouracil (FU) clearance (CL) and volume of distribution (V(ss)) are better correlated with specific body compartments, such as body cell mass (BCM), total body water (TBW) or fat free mass (FFM), rather than with body surface area (BSA) or total body weight (BW). METHODS: Thirty-four patients (13 females and 21 males) affected by colorectal cancer and receiving FU as adjuvant therapy entered the study. CL and Vss were determined after a 2 min i.v. injection of FU (425 mg m(-2)) and leucovorin (20 mg m(-2)). Body composition, in terms of BCM, TBW and FFM, was evaluated non-invasively by bioelectrical impedance analysis (BIA). RESULTS: Significant but poor correlations were found between CL or V(ss) and most anthropometric parameters, including BIA-derived measures (r2 range=0.10-0.21). However, when multiple regression analysis was performed with sex, TBW and FFM as independent variables, the correlations improved greatly. The best correlation was obtained between CL and sex (r2=0.44) and between V(ss) and sex (r2=0.36). FFM-normalized CL was significantly higher in women than in men (0.030+/-0.008 vs 0.022+/-0.005 l min(-1) kg)(-1); 95% CI of difference 0.012, 0.003; P=0.003), suggesting that FU metabolism is more rapid in females. Surprisingly, V(ss) was highly correlated with CL (r2=0.67; CL=0.52+V(ss) x 0.040). This finding may either be explained by extensive drug metabolism in extra-hepatic organs or by variable inactivation on first-pass through the lung. Both these hypotheses need experimental validation. CONCLUSIONS: The pharmacokinetics of FU are better predicted by FFM and TBW than by standard anthropometric parameters and predictions are sex-dependent. The use of BIA may lead to improved dosing with FU.
Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance.
OBJECTIVE: Our objective was to determine the influence of cytochrome P450 (CYP) 2C9 and CYP2C19 genetic polymorphisms on warfarin dose requirement and metabolic clearance. METHODS: The study population consisted of 93 Italian outpatients receiving long-term warfarin anticoagulant therapy (international normalized ratio values, 2-3), divided into 3 dose groups: low (<26.25 mg/wk; n = 37), medium (26.25-43.75 mg/wk; n = 32), and high (>43.75 mg/wk; n = 24). Steady-state unbound plasma concentrations of S- and R-warfarin were measured by HPLC and equilibrium dialysis, and corresponding unbound oral clearance (CL(free)) values were calculated. Allelic variants of CYP2C9 (CYP2C9(*)2 and CYP2C9(*)3) and CYP2C19 (CYP2C19(*)2) were identified by polymerase chain reaction, followed by restriction enzyme analysis. RESULTS: Fifty-four patients carried no CYP2C9 mutated alleles ((*)1/(*)1), 31 carried one ((*)1/(*)2, n = 15; and (*)1/(*)3, n = 16), and 8 carried two ((*)2/(*)2, n = 2; (*)3/(*)3, n = 2; and (*)2/(*)3, n = 4). Two subjects were homozygous and 19 were heterozygous for the CYP2C19(*)2 allele variant. The frequencies of CYP2C9 mutated alleles were 72% in the low-dose group, 36% in the medium-dose group, and 4% in the high-dose group; the corresponding mean S-warfarin CL(free) values were 307.5 mL/min, 480.3 mL/min, and 881.3 mL/min. The mean S-warfarin CL(free) values varied significantly among the CYP2C9 genotype groups (P <.0001), although most patients (72%) with no mutated alleles showed S-warfarin CL(free) values in the same range as those carrying mutated alleles (58-777 mL/min). No relationship was found between S-warfarin CL(free) and CYP2C19 genotype or between R-warfarin CL(free) and either CYP2C9 or CYP2C19 genotype. CONCLUSION: CYP2C9 genetic polymorphisms markedly influence warfarin dose requirements and metabolic clearance of the S-warfarin enantiomer, although nongenetic factors may also contribute to their large interindividual variability.
New limited sampling strategy for determining 5-fluorouracil area under the concentration-time curve after rapid intravenous bolus.
All limited sampling models so far proposed to determine the area under the concentration-time curve (AUC) of anticancer drugs can be applied only to the dosing/sampling schedule used to obtain the model. The authors have developed a new method to predict the AUC of 5-fluorouracil (5-FU) after rapid intravenous bolus administration of various doses, using as few as two plasma drug concentrations. The 5-FU AUC (AUC(true)) was first determined in 20 patients receiving adjuvant therapy for colorectal cancer, based on nine plasma drug concentrations obtained at 0, 2.5, 5, 10, 15, 20, 30, 45, and 60 minutes after drug administration. Ten patients received 375 mg/m(2) 5F-U + 100 mg/m(2) leucovorin and 10 received 425 mg/m(2) 5-FU + 20 mg/m(2) leucovorin. The kinetics of 5-FU was described by either a one- or two-compartment linear model, as needed. The AUC was then recalculated (AUC(approx)) using a reduced number of plasma concentrations and a simple one-compartment model. The time combinations tested were 2.5, 5, 10, and 20; 2.5, 10, and 20; 5, 10, and 20; 5 and 20; and 2.5 and 20 minutes. The accuracy and precision of the method in predicting the AUC(true) were measured by calculating the mean prediction error (MPE%) and the mean absolute error (MAE%) of the AUC(approx). MPE% ranged between -0.8% and -8.3% and MAE% between 6.1% and 9.5%, depending on the time combination used. In general, all limited sampling models tested tended to underestimate the AUC(true) slightly, particularly when 5-FU kinetics followed a two-compartment model, but bias was still within acceptable limits. The best results were obtained with plasma concentrations measured at 2.5 and 20 minutes after drug bolus (MPE%, -0.8%; MAE%, 6.1%). Although 5-FU kinetics was dose-dependent, MPE% and MAE% were not significantly different between the two groups. These data show that 5-FU AUC can be reliably predicted by using just two plasma concentrations and a one-compartment model, even when different doses are used and plasma concentration decay is biexponential.
Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis.
BACKGROUND: Plasma creatinine concentration and calculated creatinine clearance are of limited value as glomerular filtration rate (GFR) markers in patients with decompensated liver cirrhosis. We assessed plasma cystatin C as an indicator of GFR in such patients. METHODS: We studied 36 patients with decompensated liver cirrhosis and 56 noncirrhotic controls, both groups including individuals with normal and impaired renal function. GFR was measured in all individuals by inulin clearance, with values <72 mL x min(-1) x 1.73 m(-2) considered decreased. We measured cystatin C and creatinine in plasma and calculated (from plasma concentrations) and measured creatinine clearances, using for them decision points of 1.25 mg/L, 115 micromol/L, and 72 and 72 mL x min(-1) x 1.73 m(-2), respectively. RESULTS: Plasma cystatin C concentrations were similar in controls and cirrhotics and, at the usual cutpoint, could detect decreased GFR with similar sensitivities in the two groups (73% and 88%, respectively). Serum creatinine was markedly lower in cirrhotics and remained mostly within the reference interval at all GFR values; the diagnostic sensitivity of creatinine was much lower in cirrhotics than in controls (23% vs 64%). Lower diagnostic sensitivity was also observed for calculated creatinine clearance (53% vs 100% in controls), whereas similar sensitivities were found for measured creatinine clearance (86% and 81%) in controls and cirrhotics, respectively. ROC analysis showed that all four variables had similar diagnostic accuracies in cirrhotic patients. However, it also revealed that good diagnostic accuracies for plasma creatinine and calculated creatinine clearance can be obtained only if reference intervals different from those used for the general population are adopted. CONCLUSIONS: Plasma cystatin C concentration is an accurate GFR marker in cirrhotic patients. Plasma creatinine concentration and calculated creatinine clearance are of no practical value, as their reference values vary with the severity of the liver disease.
Intralesional topotecan in advanced ovarian cancer: a clinical report, based on a preclinical study.
The aim of this study was to evaluate the response of ovarian cancer to intralesionally administered topotecan. Preliminary experiments were carried out in nude mice subcutaneously grafted with three different human ovarian carcinoma cells (A2780, IGROV/DDP and SKOV-3). Topotecan was administered intravenously (i.v.: 10-15 mg/kg every 4th day for 4 times) or intralesionally (i.t.: single dose of 15-20 mg/kg) and tumor size changes/drug toxicity were evaluated. The results indicate that the sensitivity of the three tumor models was different (rank: A2780 > IGROV/DDP > SKOV-3) but, for each tumor line, the pattern of response was similar after i.v. and i.t. administration. No local toxicity was detected, but appreciable systemic toxicity (animal death rate) was observed in spite of the use of a single i.t. dose. The effects of intralesional topotecan administration were then assessed in a patient with an advanced, epithelial ovarian tumor (endometroid type, poorly differentiated histologic grade), already treated with cisplatin and paclitaxel. The treatment (7.5 mg/m(2)) was repeated three times and, although drug plasma levels were in the range generally reported following i.v. administration and typical systemic toxicity occurred, no tumor regression was observed and the patient died 14 months later. We conclude that the intralesional drug delivery is effective to achieve a rapid tumor shrinkage in large tumor lesions, but in the presence of drug resistance, either intrinsic or acquired, intratumor drug administration can not be recommended.