Disopyramide pharmacokinetics during recovery from myocardial infarction.

1 Previous pharmacokinetics studies of disopyramide in patients with ischaemic heart disease include unexplained reports of poor bioavailability and extremely long elimination half-lives which undermine accepted dosage recommendations. 2 Disopyramide pharmacokinetics were investigated after intravenous and oral administration to nine such patients. 3 Mean elimination half-life (6.82 h) and bioavailability (79.8%) were consistent with findings from a previous study in young healthy volunteers. 4 Volume of distribution was reduced by 25%: the mean +/- s.d. value was 0.61 +/- 0.17 l/kg. Total body clearance was significantly reduced: the mean +/- s.d. value was 1.02 +/- 0.16 ml min-1 kg-1. 5 These figures indicate that, in this patient group, if renal function is not significantly impaired, a standard loading dose of 2 mg/kg should be followed by the appropriate maintenance dose administered three or four times daily.     

Disopyramide in acute myocardial infarction: Problems with changing pharmacokinetics

Summary In the acute phase of myocardial infarction it is recognized that serum disopyramide concentrations may be lower than expected. This has generally been attributed to reduced oral bioavailability.This report describes data obtained routinely from 6 patients with acute myocardial infarction and cardiac dysrhythmias treated initially with intravenous disopyramide. Serum disopyramide concentrations were consistently lower than expected, on average by 2.6 µg/ml. This was interpreted as being due to relatively high drug clearance, calculated as 6.7±1.5 l/h, compared to expected values of 3–4 l/h.Dosage schedules determined on the basis of the acute phase pharmacokinetics subsequently produced higher than predicted concentrations at later times on average by 2.8 µg/ml. Clearance at this time was calculated to be 3.1±0.6 l/h.Thus even with intravenous disopyramide therapy there are problems with changing pharmacokinetic parameters after myocardial infarction.     

Disopyramide pharmacokinetics in patients with acute myocardial infarction

To study the effects of acute myocardial infarction on the pharmacokinetics of disopyramide a single oral dose of disopyramide base (200 mg) was administered to 6 patients with myocardial infarction both in the acute (Study I) and recovery (Study II) phases. An intravenous tracer dose of 14C-disopyramide (2.5 micrograms/0.3 mg) was given simultaneously with the oral dose. On the basis of the intravenous tracer data, the volume of distribution, binding to plasma proteins, total plasma clearance, renal clearance and elimination half-life of disopyramide and mono-N-dealkyl disopyramide were the same in Studies I and II. The peak serum concentrations of disopyramide after oral dosing in Studies I and II were 2.6 +/- 1.2 (SEM) and 6.4 +/- 1.9 microgram/ml, respectively (p less than 0.05), the peak times 3.29 +/- 1.22 and 1.21 +/- 0.39 h (N.S.) and the AUCINF 38.0 +/- 7.7 and 60.7 +/- 9.9 micrograms . h . ml-1 (p less than 0.05). The recovery of disopyramide in urine over 3 days averaged 46% and 47% of dose, and that of mono-N-dealkyl disopyramide 22% and 16% of the dose, respectively. Thus, the gastrointestinal absorption of disopyramide was disturbed, resulting in low plasma concentrations after oral dosing, whereas the elimination of disopyramide was unaltered in the acute phase of myocardial infarction.     

Effects of cytochrome P450 inhibitors and inducers on the metabolism and pharmacokinetics of ospemifene

Purpose: The objectives were to determine the cytochrome P450 (CYP) enzymes involved in the metabolism of ospemifene and its main hydroxylated metabolites and to examine the effects of CYP inhibitors and inducers on ospemifene pharmacokinetics. Methods: In vitro metabolism studies were conducted using human liver microsomes; CYP‐selective inhibitors and CYP‐specific substrates were used to determine the roles of nine CYP isoforms in ospemifene metabolism. Two Phase 1 clinical trials were conducted in healthy postmenopausal women; crossover designs examined the effects of pretreatment with the CYP modulators rifampicin, ketoconazole, fluconazole and omeprazole on ospemifene pharmacokinetics. Results: Although several CYP inhibitors decreased the in vitro formation of ospemifene metabolites, none of them completely blocked metabolism. Roles for CYP3A4, CYP2C9, CYP2C19 and CYP2B6 in the metabolism of ospemifene and its two main metabolites, 4‐­hydroxyospemifene and 4′‐hydroxyospemifene, were confirmed. The in vivo experiments demonstrated that ospemifene serum concentrations were decreased by rifampicin pretreatment, increased by ketoconazole or fluconazole pretreatment, and minimally affected by omeprazole pretreatment. Conclusions: The clinical pharmacokinetic findings and in vitro data suggest that CYP3A4 is important for ospemifene metabolism, but other CYP isoforms and metabolic pathways also contribute. Strong CYP3A or CYP2C9 inducers (e.g. rifampicin) would be expected to decrease the exposure to ospemifene. Ospemifene should be used with caution when coadministered with the modest CYP3A inhibitor ketoconazole and should not be coadministered with the potent CYP3A/CYP2C9/CYP2C19 inhibitor fluconazole. The potent CYP2C19 inhibitor omeprazole is unlikely to cause clinically significant changes in ospemifene pharmacokinetics. Copyright © 2013 John Wiley & Sons, Ltd.     

Disopyramide pharmacokinetics in the elderly after single oral administration

Disopyramide (D) kinetics were studied after single oral dose (200 mg) in ten elderly male patients (mean age: 75.5 yrs) without clinical or laboratory signs of hepatic, renal or cardiac disease, and in six healthy male subjects. They were all non smokers and had not taken alcohol for at least 10 days. Peak plasma concentration and area under the curve (AUCo-oo) were 54% and 51% respectively higher in the elderly group, whereas plasma half life was virtually the same in both groups (about 9 hrs). The major D metabolite, mono-N-desisopropyldisopyramide (MND), showed a tendency towards an increase of AUCo-24 h and T1/2 but did not reach the 5% significance level. Eight of the ten elderly patients but only two of the six young subjects complained of anticholinergic side effects. On the basis of the pharmacokinetic changes observed (and provided that plasma protein binding is unchanged), D oral dose should be reduced by 1/3, without modifying the dosage interval.     

The effect of verapamil on antipyrine pharmacokinetics and metabolism in man.

The effect of verapamil pre-treatment on the pharmacokinetics and metabolism of antipyrine was studied in eight healthy male volunteers. The oral clearance of antipyrine was decreased from 2.18 to 1.95 l h-1 (P less than 0.01) by verapamil (80 mg three times daily for 2 days prior to antipyrine administration and 2 days following) while half-life was increased from 13.2 to 15.6 h (P less than 0.01). The urinary excretion of norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was decreased by 19.2%, 23.1% and 16.7% respectively (P less than 0.05) in the presence of verapamil. In addition, the rate constants for formation of each of these metabolites were significantly decreased by an average of approximately 30%. These results suggest that verapamil is capable of inhibiting oxidative metabolism, a finding which could be of clinical significance for drugs highly dependent upon pathways such as those inhibited in this study for elimination.     

Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and14C-disopyramide

The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of¹⁴C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10^–7M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7X10⁵ M^–1 and 4.4X10 ⁵ M^–1, respectively (p < 0.05). The unbound clearance of disopyramide averaged 277ml/min and 209 ml/min in normal subjects and in patients (p < 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p < 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.This work was supported by Grant GM-28424 from the National Institute of General Medical Sciences, National Institutes of Health.     

The effect of probenecid on paracetamol metabolism and pharmacokinetics

Summary The influence of probenecid on the pharmacokinetics of paracetamol was investigated in a group of healthy volunteers.Pretreatment with probenecid caused a significant decrease in paracetamol clearance (6.23 to 3.42 ml·min^–1·kg^–1). The urinary excretion of paracetamol sulphate (243 to 193 mg); and paracetamol glucuronide (348 to 74.5 mg) were significantly reduced, whereas that of paracetamol was unchanged.Probenecid was shown to be an uncompetitive inhibitor of paracetamol glucuronidation in vitro, using rat liver microsomes.     

The effect of renal impairment on the pharmacokinetics and metabolism of bopindolol.

The pharmacokinetics of the non-selective beta-adrenoceptor antagonist, bopindolol, have been studied in 18 hypertensive patients with varying degrees of renal impairment following single and multiple oral dosing. Bopindolol, which undergoes extensive hepatic metabolism, was found to accumulate in patients with chronic renal failure but the disposition in patients on regular haemodialysis did not differ significantly from patients with normal renal function. The mechanism underlying these changes in pharmacokinetics is not clear but suggests the presence of metabolic inhibitors in uraemic plasma which are removed by regular haemodialysis.     

Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and 14C-disopyramide

The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of 14C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10(-7) M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7 X 10(5) M-1 and 4.4 X 10(5) M-1, respectively (p less than 0.05). The unbound clearance of disopyramide averaged 277 ml/min and 209 ml/min in normal subjects and in patients (p less than 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p less than 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.     

Stereoselective metabolism and pharmacokinetics of tegafur.

OBJECTIVES: UFT is composed of racemic tegafur (FT), a prodrug of 5-fluorouracil (5-FU), and uracil in a fixed molar combination (1:4). FT contains a chiral center and has two stereoisomers, R-FT and S-FT. The objectives of this study were to assess the stereoselectivity in the metabolism of FT to 5-FU in vitro and to determine stereoselective differences in the disposition of FT in vivo. METHODOLOGY: R-FT, S-FT, and racemic FT were incubated with pooled human liver microsomes and S-9 fraction for a period of up to 30 min for in vitro studies. For pharmacokinetics, plasma samples were obtained from fasted cancer patients over a period of 24 h after oral administration of 200 mg UFT. Samples from in vitro studies and patient plasma samples were analyzed for FT using a validated achiral and a chiral assay, and for 5-FU using a validated GC/MS assay. RESULTS: R-FT was metabolized at a rate 5.6-times faster than S-FT by human liver microsomes. Similarly, stereoselective metabolism of R-FT was also seen in the S-9 incubations. In cancer patients, the peak plasma concentrations (C(max)) and the time to reach C(max) (T(max)) were similar for the two isomers after the administration of UFT suggesting no apparent differences in their absorption kinetics. However, the area under the curve from zero to infinity [AUC(INF)] and the terminal elimination half-life (T-HALF) values for R-FT were about 4.6- and 4.4-fold lower compared to S-FT, respectively, suggesting the preferential elimination of R-FT. The T-HALF of racemic FT (8.3 h) was comparable to the T-HALF of S-FT (10.3 h) which indicated that the kinetics of the racemate are governed by S-FT. The active cytotoxic moiety, 5-FU, exhibited formation rate limited kinetics from R-FT because the T-HALF of 5-FU (3.4 h) was similar to that of R-FT (2.4 h). CONCLUSIONS: The R-isomer of FT is preferentially metabolized to 5-FU compared to the S-isomer in vitro. The distinct kinetic profiles of the stereoisomers of FT following the administration of UFT is apparently due to the stereoselective disposition of the R-isomer relative to the S-isomer. These data suggest that the R-isomer of FT is worthy of further preclinical and clinical evaluation for safety, efficacy, and pharmacokinetics.     

Bicalutamide: clinical pharmacokinetics and metabolism

Bicalutamide is a nonsteroidal pure antiandrogen given at a dosage of 150 mg once daily as monotherapy for the treatment of early (localised or locally advanced) nonmetastatic prostate cancer. It is used at a dosage of 50 mg once daily in combination with a luteinising hormone-releasing hormone analogue or surgical castration for the treatment of advanced prostate cancer. Bicalutamide is a racemate and its antiandrogenic activity resides almost exclusively in the (R)-enantiomer, with little, if any, activity in the (S)-enantiomer. (R)-Bicalutamide is slowly and saturably absorbed, but absorption is unaffected by food. It has a long plasma elimination half-life (1 week) and accumulates about 10-fold in plasma during daily administration. (S)-Bicalutamide is much more rapidly absorbed and cleared from plasma; steady-state concentrations (Css) of (R)-bicalutamide are 100-fold higher than those of (S)-bicalutamide. Css increases linearly with doses up to 50 mg, but nonlinearly at higher doses, reaching a plateau above 300 mg. Css is higher in Japanese than in Caucasians, but no relationship with degree of renal impairment, bodyweight or age exists. Although mild-to-moderate hepatic impairment does not affect pharmacokinetics, there is evidence for slower elimination of (R)-bicalutamide in subjects with severe hepatic impairment. Bicalutamide metabolites are excreted almost equally in urine and faeces with little or no unchanged drug excreted in urine; conversely, unchanged drug predominates in plasma. Bicalutamide in faeces is thought to arise from hydrolysis of bicalutamide glucuronide and from unabsorbed drug. Bicalutamide appears to be cleared almost exclusively by metabolism; this is largely mediated by cytochrome P450 (CYP) for (R)-bicalutamide, but glucuronidation is the predominant metabolic route for (S)-bicalutamide. (S)-Bicalutamide is metabolised in vitro by CYP3A4, and it is probable that this isoenzyme is also responsible for the metabolism of (R)-bicalutamide. In vitro data suggest that (R)-bicalutamide has the potential to inhibit CYP3A4 and, to a lesser extent, CYP2C9, 2C19 and 2D6. However, using midazolam as a specific CYP3A4 marker, no clinically relevant inhibition is observed in vivo with bicalutamide 150mg. Although bicalutamide is a CYP inducer in laboratory animals, dosages < or = 150 mg/day have shown no evidence of enzyme induction in humans. Daily administration of bicalutamide increases circulating levels of gonadotrophins and sex hormones; although testosterone increases by up to 80%, concentrations in most patients remain within the normal range. Bicalutamide produces a dose-related decrease in prostate-specific antigen (PSA) at dosages < or = 150 mg/day. However, little relationship is observed between median PSA reduction and (R)-bicalutamide Css.     

Lack of effect of terfenadine on theophylline pharmacokinetics and metabolism in normal subjects.

The pharmacokinetics of oral theophylline (250 mg) and the production of its metabolites (3-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid) were studied before and after the administration of oral terfenadine (120 mg twice daily for 16 days) in 10 healthy volunteers. Comparison of volumes of distribution, elimination half-lives, areas under the plasma concentration-time curves, plasma clearance of theophylline and elimination of theophylline metabolites indicated that terfenadine had no significant effect on theophylline pharmacokinetics and metabolism.     

The pharmacokinetics of mefloquine in man: lack of effect of mefloquine on antipyrine metabolism.

A method is described for the determination of the new antimalarial agent, mefloquine, in plasma and urine. After oral administration of 750 mg mefloquine to six volunteers, absorption, was apparently slow, with plasma mefloquine concentrations at 24 h (559 +/- 181 ng ml-1; mean +/- s.d.) higher than at 6 h (459 +/- 166 ng ml-1). The elimination half-life was 373 +/- 249 h, oral clearance was 5.09 +/- 2.7 1 h-1, and apparent volume of distribution was 35.7 +/- 30.7 l kg-1 (assuming 100% bioavailability). Mefloquine (750 mg) had no significant effect on salivary kinetics of antipyrine or on the metabolic clearance of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine, when antipyrine was administered either 2 h or 2 weeks after dosing with mefloquine.     

Comutagenesis-III. In vitro metabolism of 2-amino3-methylpyridine : the effect of various potential inhibitors,activators and inducers

1. The effects of various potential inhibitors,activators and inducers on the metabolism of the comutagen 2-amino- 3-methylpyridine(2A3MP) by rabbit hepatic microsomes and S9 supernatants have been studied. 2. The 1-N-oxidation of 2A3MP to 2-amino- 3-methylpyridine- 1-N-oxide (2A3MPNO) was inhibited by 2,4-dichloro- 6-phenylphenoxyet hylamine (DPEA), 2-diethylaminoethyl- 2,2-diphenylvalerat e (SKF 525-A) and n-octylamine. 3. The C-oxidation products of 2A3MP, i.e. 2-amino- 3-hydroxymethylpy ridine (2A3HMP) and 2-amino- 3-methyl- 5-hydroxypyridine (2A3M5HP), were also inhibited by these compounds. 4. Pretreatment of animals with phenobarbitone (PB) resulted in an increase in the production of 2A3MPNO and 2A3HMP, whereas β-naphthoflavone (BNF) pretreatment had a greater effect on the formation of 2A3M5HP. 5. Pretreatment with pyridine or pyrazine also had an appreciable effect on the formation of 2A3HMP. 6. It is suggested that different cytochrome P450 isozymes are responsible for the metabolic profile of 2A3MP. CYP2B was involved in the N-oxidation; 2E and or 2B in the formation of 2A3HMP, and 3A and or 1A in the formation of 2A3M5HP.     

Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.

1 Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration (2 mg/kg) and oral administration (300 mg) of the two commercially available preparations, Rythmodan (Roussel Laboratories) and Norpace (Searle Laboratories). 2 An open one compartment body model adequately described the kinetics of disopyramide in serum and urine. 3 After intravenous administration, the following average pharmacokinetic parameters were found: biological half-life, 7.8 h; total clearance, 95 ml/min; renal clearance, 54 ml/min; apparent volume of distribution, 60 litres. 4 After oral Rythmodan and Norpace, serum concentration profiles and urinary excretion data revealed significant differences in rates of absorption, times required to achieve peak serum concentrations and biological half-lives. These differences were largely due to the relatively slow absorption characteristics of Norpace. 5 The absence of hysteresis in plots of QT prolongation against disopyramide serum concentration after oral administration indicated that serum and pharmacologic effect kinetics were indistinguishable within a kinetically equivalent compartment. 6 Analysis of both serum and urine data showed that while Norpace had a significantly higher degree of bioavailability (P less than 0.005), the 5--15% difference between the two formulations should not normally be of any clinical significance.