Predictive performance of three practical approaches for grapefruit juice-induced 2-fold or greater increases in AUC of concomitantly administered drugs.

WHAT IS KNOWN AND OBJECTIVE: Clinical pharmacists have a challenging task when answering patients' question about whether they can take specific drugs with grapefruit juice (GFJ) without risk of drug interaction. To identify the most practicable method for predicting clinically relevant changes in plasma concentrations of orally administered drugs caused by the ingestion of GFJ, we compared the predictive performance of three methods using data obtained from the literature. METHODS: We undertook a systematic search of drug interactions associated with GFJ using MEDLINE and the Metabolism & Transport Drug Interaction Database (DIDB version 4.0). We considered an elevation of the area under the plasma concentration-time curve (AUC) of 2 or greater relative to the control value [AUC ratio (AUCR) ≥ 2.0] as a clinically significant interaction. RESULTS AND DISCUSSION: The data from 74 drugs (194 data sets) were analysed. When the reported information of CYP3A involvement in the metabolism of a drug of interest was adopted as a predictive criterion for GFJ-drug interaction, the performance assessed by positive predictive value (PPV) was low (0.26), but that assessed by negative predictive value (NPV) and sensitivity was high (1.00 for both). When the reported oral bioavailability of ≤ 0.1 was used as a criterion, the PPV improved to 0.50 with an acceptable NPV of 0.81, but sensitivity was reduced to 0.21. When the reported AUCR was ≥ 10 after co-administration of a typical CYP3A inhibitor, the corresponding values were 0.64, 0.79 and 0.19, respectively. WHAT IS NEW AND CONCLUSION: We consider that an oral bioavailability of ≤ 0.1 or an AUCR of ≥ 10 caused by a CYP3A inhibitor of a drug of interest may be a practical prediction criterion for avoiding significant interactions with GFJ. Information about the involvement of CYP3A in their metabolism should also be taken into account for drugs with narrow therapeutic ranges.

Longitudinal monitoring of CYP3A activity in patients receiving 3 cycles of itraconazole pulse therapy for onychomycosis.

WHAT IS KNOWN AND OBJECTIVE: Itraconazole, a CYP3A inhibitor, is used for the treatment for onychomycosis with a three-cycle pulse therapy over 3 months, but its effects on in vivo CYP3A activity during the entire course remain unknown. METHODS: Urinary 6ß-hydroxycortisol/cortisol ratios were determined in 19 patients with onychomycosis, before therapy, during three cycles of itraconazole pulse therapy (200 mg twice daily for a week in each monthly cycle) and at 3 month after completion of therapy. RESULTS AND DISCUSSION: The mean 6ß-hydroxycortisol/cortisol ratio was reduced by 68% from baseline (P < 0·05) after the 1st pulse dosing, but the inhibitory effect appeared to be resolved before the next pulse dosing and at 3 months post-treatment. The magnitude of inhibition appeared in proportion to the baseline CYP3A activity. WHAT IS NEW AND CONCLUSION: The inhibitory effect of itraconazole pulse therapy on the in vivo CYP3A activity appears clinically relevant at the end of each cycle, but the inhibition resolves, on average, within 3 weeks.

Acute kidney injury after myeloablative cord blood transplantation in adults: the efficacy of strict monitoring of vancomycin serum trough concentrations.

BACKGROUND: Acute kidney injury (AKI) is a common medical complication after myeloablative allogeneic stem cell transplantation (SCT). We have previously performed a retrospective analysis of AKI after cord blood transplantation (CBT) in adults, and found that the maximum of vancomycin (VCM) trough levels were significantly higher in patients with AKI. Following these results, we have monitored VCM serum trough concentrations more strictly, to not exceed 10.0 mg/L, since 2008. METHODS: In this report, we performed an analysis of AKI in a new group of 38 adult patients with hematological malignancies treated with unrelated CBT after myeloablative conditioning between January 2008 and July 2011. RESULTS: Cumulative incidence of AKI at day 100 after CBT was 34% (95% confidence interval 19-50). The median of the maximum value of VCM trough was 8.8 (4.5-12.2) mg/L. In multivariate analysis, no factor was associated with the incidence of AKI. No transplant-related mortality was observed. The probability of disease-free survival at 2 years was 83%. CONCLUSION: These findings suggest that strict monitoring of VCM serum trough concentrations has a beneficial effect on outcomes of CBT.

A novel microsatellite polymorphism of sodium channel beta1-subunit gene (SCN1B) may underlie abnormal cardiac excitation manifested by coved-type ST-elevation compatible with Brugada syndrome in Japanese.

OBJECTIVE: Brugada syndrome (BrS) is a rare sodium channelopathy typically seen in middle-aged, Southeast Asian males conferring high risks of cardiac sudden death. Loss-of-function mutations in SCN5A encoding the alpha-subunit of cardiac sodium channels may account partially for its etiology. We aimed to study whether mutations in the beta-subunits of sodium channel (SCN1B and SCN2B) would also be associated with abnormal cardiac excitation in BrS. METHODS: 85 Japanese patients suspected to have BrS undertook a diagnostic challenge test with a sodium channel blocker, pilsicainide. Genetic screenings were performed for SCN5A, SCN1B and SCN2B by PCR-SSCP and direct sequence of amplicons in the patients and 50 healthy controls. RESULTS: 30 patients exhibited BrS-like ECG pattern (i.e., a coved-type ST-segment elevation) either at baseline or after the drug challenge. Genetic screenings revealed a sequence variation (p.R190Q) and 3 polymorphisms (p.H558R, p.R1193Q, IVS24+53T > C) in SCN5A, a sequence variation (g.-26G > T) and 2 polymorphisms (IVS1+53G > T and IVS3 +2996(TTA)8-15) in SCN1B and 2 polymorphisms (IVS2+27A > G, IVS2+76G > A) in SCN2B. A logistic analysis revealed that male, middle age (40 - 59 years of age) and IVS3+2996(TTA)8 of SCN1B were significantly (p < 0.05) associated with the development of BrS-like ECG pattern with odds ratios (95% confidence intervals) of 5.9 (1.8 - 19.6), 2.9 (1.4 - 6.1) and 2.3 (1.1 - 4.9), respectively. While the IVS3+2996(TTA)8 allele has not been reported in Caucasians previously, its allelic frequency in the patients exhibiting the BrS-like ECG pattern (0.250) was comparable to that in the healthy controls (0.260). CONCLUSION: The IVS3+ 2996(TTA)8 allele commonly seen in Japanese would not be pathogenic itself but may render male, middle-aged Japanese more susceptible to BrS.

Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes.

To study whether an in-vitro model for three different genotypes of human CYP2C9*3 polymorphism would be useful for predicting the in-vivo kinetics of (S)-warfarin in patients with the corresponding genotypes, the intrinsic clearance (Cl(int) or Vmax/Km) for (S)-warfarin 7-hydroxylation obtained from recombinant human CYP2C9*1 [wild-type (wt)] and CYP2C9*3 (Leu359/Leu) expressed in yeast and the mixture of equal amounts of these were compared with the in-vivo unbound oral CI (CI(po,u)) of (S)-warfarin obtained from 47 Japanese cardiac patients with the corresponding CYP2C9 genotypes. The in-vitro study revealed that the recombinant CYP2C9*1 (wt/wt), 2C9*3 (Leu359/Leu) and their mixture (Ile359/Leu) possessed a mean Km of 2.6, 10.4 and 6.6 microM and Vmax of 280, 67 and 246 pmol/min/nmol P450, respectively. Thus, the mean in-vitro Cl(int) obtained from recombinant CYP2C9*3 (Leu359/Leu) and the mixture (Ile359/Leu) of 2C9*3 and 2C9*1 were 94% and 65% lower than that obtained from CYP2C9*1 (wt/wt) (6.7 versus 38 versus 108 ml/min/micromol P450, respectively). The in-vivo study showed that the median Cl(po,u) for (S)-warfarin obtained from patients with homozygous (Leu359/Leu, n = 1) and heterozygous (Ile359/Leu, n = 4) CYP2C9*3 mutations were reduced by 90% (62 ml/min) and 66% (212 ml/min, P < 0.05) compared with that obtained from those with homozygous 2C9*1 (625 ml/min, n = 42). Consequently, there was a significant correlation (r = 0.99, P < 0.05) between the in-vitro Cl(int) for (S)-warfarin 7-hydroxylation and the in-vivo Cl(po,u) for (S)-warfarin in relation to the CYP2C9*3 polymorphism. In conclusion, the in-vitro model for human CYP2C9*3 polymorphism using recombinant cytochrome P450 proteins would serve as a useful means for predicting changes in in-vivo kinetics for (S)-warfarin and possibly other CYP2C9 substrates in relation to CYP2C9*3 polymorphism.

Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism.

After the oral administration of 160 mg pseudoracemic verapamil (80 mg dideuterodextro (d) isomer and 80 mg levo (l) isomer), the prolongation of the PR interval was assessed in relation to d- and l-verapamil plasma concentrations. Concentration-effect curves were analyzed with the sigmoidal Emax model. Because of stereoselective first-pass metabolism, the mean plasma d- to l-verapamil concentration ratio of 4.5 +/- 1.2 was substantially greater than that of 2.1 +/- 0.3 after intravenous dosing. Compared with the concentration after intravenous injection, the total verapamil concentration after oral dosing consisted of a substantially smaller proportion of the more potent l-isomer. These differences in isomer composition of the total verapamil plasma concentration as a result of the route of administration explain the diminished negative dromotropic potency of racemic verapamil after oral dosing. The concentration required to reach 50% of the maximum effect (EC50) for total verapamil concentration was 129.0 +/- 22.9 ng/ml, which was more than three times higher than that after intravenous injection. To assess the relative contributions of the d- and l-isomers to overall dromotropic potency, changes in the PR interval were measured after separate oral dosing with 250 mg d-verapamil and 100 mg l-verapamil. The EC50 showed an 11-fold difference between the l- (36.9 +/- 14.7 ng/ml) and d- (363.1 +/- 64.2 ng/ml) isomers. The EC50 for the l-isomer concentration after oral pseudoracemic verapamil (20.2 +/- 6.3 ng/ml) did not differ significantly from that after l-verapamil alone (36.9 +/- 14.7 ng/ml). We conclude that the l-isomer determines the negative dromotropic effects of verapamil and that the d-isomer is of minor importance.

Plasma famotidine concentration versus intragastric pH in patients with upper gastrointestinal bleeding and in healthy subjects.

To study the concentration-response relationship of famotidine, we serially monitored intragastric pH and measured plasma drug concentrations simultaneously after an intravenous injection of this H2-receptor antagonist (0.1 mg/kg) in eight patients with upper gastrointestinal bleeding and in six healthy subjects. By applying the sigmoidal Emax model the mean (+/- SD) plasma famotidine concentrations associated with an intragastric pH of 4.0 in patients and healthy subjects were estimated to be 17.7 +/- 10.7 and 24.8 +/- 10.3 ng/ml, respectively (not significantly different). No significant differences were observed in the mean pharmacokinetic parameters between the two study groups. Multiple regression analysis revealed that not only a pharmacokinetic factor (i.e., elimination t1/2) but also a pharmacodynamic (or sensitivity) factor (i.e., a drug concentration associated with an intragastric pH of 4.0) contributed significantly (p less than 0.01) to the overall variability in the duration of antisecretory effect in our study subjects, with standardized partial regression coefficients of 0.54 and -0.63, respectively. Based on these data, we predict that around-the-clock control of a fasting intragastric pH above 4.0 can be attained by a continuous infusion of famotidine at rates ranging from 6 to 25 mg/day (mean +/- SD, 11 +/- 7 mg/day) in a 70 kg patient whose pharmacokinetic and pharmacodynamic characteristics are similar to those of our patients.

Protein binding of disopyramide in liver cirrhosis and in nephrotic syndrome.

The plasma protein binding of disopyramide (D) was determined in seven patients with cirrhosis, six with nephrotic syndrome, and seven healthy subjects. Plasma samples containing concentrations of 0.2 to 12.0 micrograms/ml were ultrafiltered and the free fractions were measured with fluorescence polarization immunoassay. The mean free fractions at D concentrations ranging from 1 to 6 micrograms/ml were significantly (P less than 0.01) greater in patients with cirrhosis than in healthy subjects. No difference was observed between patients with nephrotic syndrome and healthy subjects. The free fraction at D 3 micrograms/ml correlated better with alpha 1-acid glycoprotein (r = -0.77) than with albumin (r = -0.46). Patients with cirrhosis had significantly (P less than 0.01) lower capacity constants as compared with the other two study groups. There was a significant (P less than 0.01) correlation between capacity constant and alpha 1-acid glycoprotein (r = 0.71). Our results suggest that the D therapeutic range measured as the total plasma concentration in cirrhosis, but not in nephrosis, should be approximately 50% lower than previously believed.

Effects of a sustained thromboxane synthase inhibition on exercise-induced changes in eicosanoid formation, catecholamine concentration, and platelet aggregation in humans.

In an effort to characterize an interaction between the eicosanoids and sympathoadrenal system on platelet aggregation, we tried to determine if a sustained thromboxane A2 (TXA2) synthase inhibition would modulate changes in eicosanoid formation, catecholamine concentration, and platelet aggregation induced by a physical stress. We measured thromboxane B2 (TXB2), 11-dehydro-TXB2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), norepinephrine, and epinephrine in vivo and platelet aggregation ex vivo before and after a treadmill exercise with and without the oral doses (400 mg twice daily for 7 days) of a new selective TXA2 synthase inhibitor (DP-1904) in nine healthy male subjects. The exercise tests performed on the pretreatment day (day 0) and posttreatment day (day 7) gave a similar result. DP-1904 caused a decrease in serum and urinary TXB2 and urinary 11-dehydro-TXB2 (p less than 0.001 to p less than 0.01) and an increase in serum 6-keto-PGF1 alpha (p less than 0.001 to p less than 0.05) throughout the dosing interval on days 4 and 7. Despite the drug effect on eicosanoid formation at rest and after exercise, the exercise-induced plasma norepinephrine and epinephrine concentrations did not differ between days 0 and 7. The 7-day treatment decreased (p less than 0.01) platelet aggregation induced both by adenosine diphosphate and by collagen at rest. However, the exercise increased (p less than 0.01) platelet aggregation by the two aggregators, resulting in the disappearance of the drug-induced antiaggregatory effects observed at rest. The treatment with a TXA2 synthase inhibitor does not appear to attain the antithrombotic action during an exercise despite the occurrence of a sustained endoperoxide shunting.

Disposition kinetics and dynamics of nicainoprol, a new antiarrhythmic agent, in humans.

Kinetics and resting and exercise-induced hemodynamic and ECG effects of nicainoprol, a new antiarrhythmic structurally resembling propafenone or propranolol, were investigated in eight healthy male subjects receiving a 1-hour infusion (100 mg) and oral dose (200 mg) in a randomized-crossover fashion. Nicainoprol in plasma and urine was determined by a specific HPLC assay. Plasma concentration-time data were fitted to a triexponential equation. Mean postinfusion kinetic data were: alpha-phase half-life = 3.1 minutes, beta-phase half-life = 106.6 minutes, and gamma-phase half-life = 12.4 hours; volume of central compartment = 0.114 L/kg; steady-state volume of distribution = 0.67 L/kg; total clearance = 3.6 ml/min/kg; and renal clearance = 0.56 ml/min/kg. Absolute bioavailability was approximately 70% and peak plasma drug concentration occurred 2.3 hours after oral administration. Interindividual variability in AUC was 1.6- and 2.4-fold after intravenous and oral administration, respectively. Cumulative fraction excreted unchanged in urine was approximately 15% and 9% of the dose after intravenous and oral administration, respectively. Resting heart rates were increased, whereas exercise-induced heart rates were unchanged after both doses. QRS durations were widened after both doses. PR and QTc intervals were prolonged during intravenous study. The results suggest that nicainoprol is an enzyme-limited or poorly extracted drug suitable for both intravenous and oral administration and devoid of beta-blocking action in humans, at least with doses tested in this study. Its ECG properties appear to be similar to those of class I antiarrhythmics.

Famotidine-associated central nervous system reactions and plasma and cerebrospinal drug concentrations in neurosurgical patients with renal failure.

Central nervous system toxicity of H2-receptor antagonists has rarely been confirmed by the respective elevated cerebrospinal fluid drug concentrations. We observed two hemodialyzed neurosurgical patients in whom mental deterioration and convulsions developed after intravenous famotidine therapy (10 and 40 mg/day). Their cerebrospinal fluid drug concentrations were grossly elevated (i.e., 160 and 249 ng/ml) compared with those obtained from three other hemodialyzed neurosurgical patients who exhibited no central nervous system reactions (i.e., 47 to 85 ng/ml). In addition, the mean cerebrospinal fluid/plasma drug concentration ratio obtained from these five neurosurgical patients with renal failure (i.e., 0.46) and that from 10 other neurosurgical patients with normal renal function (i.e., 0.41) were about four times greater than that previously reported from non-neurosurgical patients with normal renal function (i.e., 0.12). Our observation suggests that patients with not only renal dysfunction but also following neurosurgical operations have an excessive accumulation of famotidine in the central nervous system and are more susceptible to the drug-induced adverse central nervous system reactions.

Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes.

OBJECTIVE: To determine whether genetic polymorphism of cytochrome P450 (CYP) 2C9 affects the in vivo metabolism of warfarin enantiomers. METHODS: Eighty-six Japanese patients heart disease who were given warfarin participated in the study. Plasma unbound concentrations of warfarin enantiomers and urinary (S)-7-hydroxywarfarin concentrations were measured by means of a chiral HPLC and ultrafiltration technique to calculate the unbound oral clearance (CLpo,u) for the enantiomers and the formation clearance (CLm) for (S)-warfarin 7-hydroxylation. Genotyping for CYP2C9 (the wild type [wt], Arg144/Cys, and I1e359/Leu) and for CYP2C19 (wt, ml, and m2) was performed with a polymerase chain reaction method. RESULTS: Three patients were heterozygous for the CYP2C9 Leu359 mutation but none were homozygous for the mutation (the allele frequency of 0.017). None had a CYP2C9 Cys144 allele. The medians for (S)-warfarin CLpo,u and its 7-hydroxylation CLm obtained from heterozygotes of CYP2C9 Leu359 were significantly less than those obtained from homozygotes of the wt allele, as follows: 234 ml/min (range, 156 to 269 ml/min) versus 632 ml/min (range, 180 to 2070 ml/min) (p < 0.001) and 0.20 ml/min (range, 0.05 to 0.77 ml/min) versus 0.80 ml/min (range, 0.05 to 14.9 ml/min) (p < 0.05), respectively. In contrast, no difference was observed in (R)-warfarin CLpo,u between the groups. The allele frequencies for CYP2C19 m1 and CYP2C19 m2 were 0.26 and 0.14, respectively, indicating 15% of patients were genotypically poor metabolizers of CYP2C19. No difference in CLpo,u for warfarin enantiomers was observed between the assumed CYP2C19 phenotypes. CONCLUSION: Heterozygotes for CYP2C9 I1e359/Leu allele have reduced in vivo metabolism of (S)-warfarin but not (R)-warfarin. Because (S)-warfarin has a greater anticoagulant potency than its (R)-congener, the genetic polymorphism of CYP2C9 may partly account for the large interpatient variability in therapeutic dosages of warfarin.

Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone.

OBJECTIVE: To clarify the mechanism(s) for the interaction between warfarin and benzbromarone, a uricosuric agent, and to predict changes in the in vivo pharmacokinetics of (S)-warfarin from in vitro data. METHODS: Warfarin enantiomers and benzbromarone in serum, 7-hydroxywarfarin in urine, and serum unbound fractions of warfarin enantiomers were measured in patients with heart disease given warfarin with (n = 13) or without (n = 18) oral benzbromarone (50 mg/d). In vitro inhibition constants (K(i)) of benzbromarone for (S)-warfarin 7-hydroxylation were determined with use of human CYP2C9 and liver microsomes. The magnitude of changes in the formation clearance for 7-hydroxylation (CLf), the unbound oral clearance (CL(oral,u)), and the oral clearance (CL(oral)) for (S)-warfarin were predicted by equations incorporating the in vitro Ki, the theoretical maximum unbound hepatic benzbromarone concentration, and the fractions of warfarin eliminated through metabolism and of CYP2C9-mediated metabolic reaction susceptible to inhibition by benzbromarone. RESULTS: The patients given warfarin with benzbromarone required a 36% less (P < .01) warfarin dose than those given warfarin alone (2.5 versus 3.9 mg/d) to attain similar international normalized ratios (2.1 and 2.2, respectively), and the former had 65%, 53%, and 54% lower (P < .05 or P < .01) CLf, CL(oral),u, and CL(oral) for (S)-warfarin than the latter, respectively. In contrast, no significant differences were observed for (R)-warfarin kinetics between the groups. Benzbromarone was found to be a potent competitive inhibitor (Ki < 0.01 micromol/L) for (S)-warfarin 7-hydroxylation mediated by CYP2C9. The average changes in the in vivo CLf, CL(oral),u, and CL(oral)values for (S)-warfarin induced by benzbromarone were largely predictable by the proposed equations. CONCLUSION: Benzbromarone would intensify anticoagulant response of warfarin through an enantioselective inhibition of CYP2C9-mediated metabolism of pharmacologically more potent (S)-warfarin. The magnitude of changes in the in vivo warfarin kinetics may be predicted by in vitro data.

Developmental changes in pharmacokinetics and pharmacodynamics of warfarin enantiomers in Japanese children.

OBJECTIVE: To clarify developmental changes in the pharmacokinetics and dynamics of warfarin enantiomers to establish rational pediatric dosage. METHODS: Plasma concentrations of unbound warfarin enantiomers, vitamin K1 and vitamin K-dependent proteins (that is, prothrombin fragments 1+2, protein C, and the protein-induced by vitamin K absence) and international normalized ratio were measured in 38 prepubertal (1 to 11 years), 15 pubertal (12 to 18 years), and 81 adult (37 to 76 years) patients given long-term warfarin therapy. Unbound oral clearance values for warfarin enantiomers and its body weight-, body surface area-, and liver weight-normalized values, as well as the pharmacodynamic parameters, were compared among the groups. RESULTS: The prepubertal, pubertal, and adult patients exhibited comparable mean plasma concentrations of unbound warfarin enantiomers for pharmacologically more active (S)-warfarin. Although the unbound oral clearance of (S)-warfarin for the prepubertal patients was significantly (P < .01) less than that for the adult group (346 versus 637 mL/min), the body weight-normalized unbound oral clearance for the prepubertal patients was significantly (P < .01) greater than that for the adults and showed a negative correlation (P < .05) with age. In contrast, no differences were observed in the liver weight-normalized unbound oral clearance for (S)-warfarin between the prepubertal and adult groups. The prepubertal patients showed significantly (P < .01 or .05) lower plasma concentrations of protein C and prothrombin fragments 1+2 and greater international normalized ratio and international normalized ratio/dose than the adults. In contrast, the pubertal patients showed largely similar pharmacokinetic and pharmacodynamic properties to adults. CONCLUSION: Liver weight may be a better parameter than body weight for estimating the warfarin doses for prepubertal patients on the basis of the corresponding adult values. Augmented responses to warfarin in children should also be taken into account for estimating warfarin doses for children.

Clinical pharmacokinetics of verapamil, nifedipine and diltiazem.

The calcium antagonists diltiazem, nifedipine and verapamil are widely used in the treatment of coronary heart disease, arterial hypertension, certain supraventricular tachyarrhythmias and obstructive hypertrophic cardiomyopathy. During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 calcium antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities (diltiazem 40 to 50%; nifedipine 40 to 50%; verapamil 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In patients with liver cirrhosis the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas renal disease has no impact on the pharmacokinetics of diltiazem and verapamil, elimination half-life of nifedipine increases in relation to the degree of renal impairment due to an increase in volume of distribution. Systemic clearance, however, remains unchanged. The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of calcium antagonists, it is doubtful whether therapeutic drug monitoring will be of great value. Calcium antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between digoxin and these drugs is of clinical importance. Verapamil and diltiazem cause a significant increase in plasma digoxin concentrations. In contrast, nifedipine does not lead to a significant increase in the plasma digoxin concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal digoxin clearance.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical pharmacokinetics of famotidine.

Famotidine is a potent histamine H2-receptor antagonist widely used in the treatment and prevention of peptic ulcer disease. After intravenous administration the plasma famotidine concentration-time profile exhibits a biexponential decay, with a distribution half-life of about 0.18 to 0.5h and an elimination half-life of about 2 to 4h. The volume of distribution of the drug at steady-state ranges from 1.0 to 1.3 L/kg; plasma protein binding is low (15 to 22%). Famotidine is 70% eliminated unchanged into urine after intravenous administration. The total body and renal clearances of famotidine correlate significantly with creatinine clearance. Because its renal clearance (15 L/h) far exceeds the glomerular filtration rate, famotidine is considered to be eliminated not only via glomerular filtration but also via renal tubular secretion. Since its clearance is reduced in patients with renal insufficiency and in elderly patients, the maintenance dosage should be reduced in these patient groups. Removal of famotidine by any of the currently employed blood purification procedures (haemodialysis, peritoneal dialysis and haemofiltration) does not occur to a clinically significant degree. Liver cirrhosis does not appear to affect the disposition of famotidine unless severe renal insufficiency coexists. After oral administration, peak plasma concentrations are attained within 2 to 4h; the oral bioavailability ranges from 40 to 50%, due mainly to incomplete absorption. The oral absorption of the drug is dose-independent within a range of 5 to 40 mg. There are 3 formulations available (tablet, capsule and suspension), which appear to be bioequivalent. Coadministration of potent antacids reduces the oral absorption of famotidine by 20 to 30%. On a weight-to-weight basis, the antisecretory effect of famotidine is about 20 and 7.5 times more potent than those of cimetidine and ranitidine, respectively. Plasma famotidine concentrations correlate with its antisecretory effect: values of about 13 and 20 micrograms/L produce a 50% reduction in the gastrin-stimulated gastric acid secretion and a fasting intragastric pH of greater than 4, respectively. Available data suggest that famotidine interacts neither with the hepatic oxidative drug metabolism nor with the tubular secretion of other commonly used therapeutic agents. However, further studies are required to evaluate a full spectrum of its drug interaction potential.

Pharmacogenetics of warfarin elimination and its clinical implications.

Warfarin is one of the most widely prescribed oral anticoagulants. However, optimal use of the drug has been hampered by its >10-fold interpatient variability in the doses required to attain therapeutic responses. Pharmacogenetic polymorphism of cytochrome P450 (CYP) may be associated with impaired elimination of warfarin and exaggerated anticoagulatory responses to the drug in certain patients. Clinically available warfarin is a racemic mixture of (R)- and (S)-warfarin, and the (S)-enantiomer has 3 to 5 times greater anticoagulation potency than its optical congener. Both enantiomers are eliminated extensively via hepatic metabolism with low clearance relative to hepatic blood flow. CYP2C9 is almost exclusively responsible for the metabolism of the pharmacologically more active (S)-enantiomer. Several human allelic variants of CYP2C9 have been cloned, designated as CYP2C9*1 (reference sequence or wild-type allele), CYP2C9*2, CYP2C9*3 and CYP2C9*4, respectively. The allelic frequencies for these variants differ considerably among different ethnic populations. Caucasians appear to carry the CYP 2C9*2 (8 to 20%) and CYP2C9*3 (6 to 10%) variants more frequently than do Asians (0% and 2 to 5%, respectively). The metabolic activities of the CYP2C9 variants have been investigated in vitro. The catalytic activity of CYP2C9*3 expressed from cDNA was significantly less than that of CYP2C9*1. Human liver microsomes obtained from individuals heterozygous for CYP2C9*3 showed significantly reduced (S)-warfarin 7-hydroxylation as compared with those obtained from individuals genotyped as CYP2C9*1. The influence of the CYP2C9*3 allele on the in vivo pharmacokinetics of (S)-warfarin has been studied in Japanese patients. Patients with the homozygous CYP2C9*3 genotype, as well as those with the heterozygous CYP2C9*1/*3 genotype, had significantly reduced clearance of (S)-warfarin (by 90 and 60%, respectively) compared with those with homozygous CYP2C9*1. The maintenance dosages of warfarin required in Japanese patients with heterozygous and homozygous CYP2C9*3 mutations were significantly lower than those in patients with CYP2C9*1/*1. In addition, 86% of British patients exhibiting adequate therapeutic responses with lower maintenance dosages of warfarin (<1.5 mg/day) had either the CYP2C9*2 or CYP2C9*3 mutation singly or in combination, whereas only 38% of randomly selected patients receiving warfarin carried the corresponding mutations. Furthermore, the former group showed more frequent episodes of major bleeding associated with warfarin therapy. These data indicate that the CYP2C9*3 allele may be associated with retarded elimination of (S)-warfarin and the resulting clinical effects. However, relationships between CYP2C9 genotype, enzyme activity, metabolism of probe substrates, dosage requirements and bleeding complications should be interpreted with caution, and further studies are required.

Hemofiltrability of H2-receptor antagonist, famotidine, in renal failure patients.

To determine if a new H2-receptor antagonist, famotidine, would be significantly removed by arteriovenous hemofiltration, we measured plasma concentrations and amounts of the drug recovered in ultrafiltrate during 18 sessions of an intermittent hemofiltration performed in five patients with renal failure receiving the repeated intravenous dosings of the drug (5-20 mg/day). Plasma and ultrafiltrate drug concentrations were determined by using a high performance liquid chromatography with fluorescent detection. The mean (+/- SD) amount of the drug removed by the procedure, which was performed at the mean ultrafiltration rate of 19.0 +/- 6.0 ml/min over the mean duration of 212 +/- 168 min, corresponded to 4.1 +/- 2.2% of the daily maintenance doses. There was a significant (r = 0.90, P less than .01) linear relationship between the hemofiltration clearance and the ultrafiltration rate, indicating that the sieving coefficient, an index filtration efficiency, for the drug was largely constant (i.e., 0.73 +/- 0.10) over the ranging filtration rates (i.e., 3.9-29.5 mL/min) employed in the present study. When the mean filtration efficiency of 0.73 obtained from the study is extrapolated into a 24-hour continuous arteriovenous hemofiltration performed at commonly used filtration rates (i.e., 6-12 ml/min), the 24-hour hemofiltration clearances are estimated to range from 4 to 9 ml/min. These clearance values are found to correspond to only 10 to 25% of the mean total body clearance (about 35 ml/min) reported from anuric patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemofiltrability of histamine H2-receptor antagonist, nizatidine, and its metabolites in patients with renal failure.

To study if an H2-receptor antagonist, nizatidine, and its metabolites [N-2-monodesmethylnizatidine (N-2-MDMN) and nizatidine sulfoxide (nizatidine S-Ox)] would be removed by an arteriovenous hemofiltration, the authors measured their plasma concentrations and amounts recovered in ultrafiltrate during 11 sessions of an intermittent hemofiltration performed in seven patients with renal failure who were given an oral administration of nizatidine (150 mg). The concentrations of the parent drug and its metabolites in plasma and ultrafiltrate were determined with a high-performance liquid chromatography with ultraviolet absorbance detection. The mean (+/- standard deviation [SD]) amounts of nizatidine removed by the procedure performed at the mean ultrafiltration rate of 18 (range, 11-25) mL/min over the mean duration of 179 (60 to 300) minutes accounted for 1.9 +/- 1.4% of the dose administered. The corresponding values for N-2-MDMN and nizatidine S-Ox were 0.3 +/- 0.2% and 0.2 +/- 0.2% of the molar dose of nizatidine, respectively. There was a significant correlation between the filtration rate and the hemofiltration clearance of nizatidine (r = .94, P < .001) or its active metabolite, N-2-MDMN (r = 0.83, P < .01), indicating that the sieving coefficient (Sc), an index of filtration efficiency, for these compounds is largely constant (0.59 and 0.67 for nizatidine and N-2-MDMN, respectively) under the current hemofiltration conditions.(ABSTRACT TRUNCATED AT 250 WORDS)