Pharmacokinetics and pharmacodynamics of tenecteplase: results from a phase II study in patients with acute myocardial infarction

Tenecteplase is a site-specific engineered tissue plasminogen activator (t-PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose-ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t-PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt-PA as the accelerated 90-minute infusion regimen in this randomized, open-label study. Tenecteplase and r-tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half-life of 22 minutes and a mean terminal half-life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt-PA has a fourfold faster plasma clearance. Pharmacokinetic-pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r-tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt-PA, allowing dosing as an i.v. bolus injection. Weight-adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.     

Tenecteplase (TNK tissue plasminogen activator): A new fibrinolytic for the acute treatment of myocardial infarction

Tenecteplase, a new fibrinolytic with longer plasma half-life and greater specificity for fibrin than alteplase, achieves rapid thrombolysis in patients with acute myocardial infarction. Similar TIMI grade 3 flow rates at 90 minutes have been observed with tenecteplase and alteplase. The efficacy and safety of tenecteplase have been confirmed in a large trial, ASSENT-2, demonstrating similar mortality rates at 30 days and a lower rate of noncerebral bleeding complications when compared with alteplase. The convenience of a single bolus treatment may facilitate the initiation of early and efficient reperfusion. (c) 2001 Prous Science. All rights reserved.     

Safety and efficacy of tenecteplase in acute myocardial infarction

The use of intravenous thrombolytic agents has revolutionised the treatment of acute myocardial infarction. However, the improved mortality achieved with these drugs is tempered by the risk of serious bleeding complications, especially intracranial haemorrhage (ICH). Tenecteplase (TNKase?, Genetech Inc.) is an engineered variant of alteplase (Activase^®, Genentech Inc.) designed to have increased fibrin specificity, greater efficacy and a longer half-life. The longer half-life of tenecteplase compared to alteplase allows for convenient single bolus administration of the drug. In addition, tenecteplase dosing is based on actual or estimated patient weight, which enhances both the safety and efficacy outcomes. Large clinical trials have demonstrated equivalence in mortality and ICH between tenecteplase and alteplase. Compared to alteplase, tenecteplase use leads to lower rates of bleeding complications and a decreased risk of ICH among low weight, elderly women.     

Safety and efficacy of tenecteplase in acute myocardial infarction

The use of intravenous thrombolytic agents has revolutionised the treatment of acute myocardial infarction. However, the improved mortality achieved with these drugs is tempered by the risk of serious bleeding complications, especially intracranial haemorrhage (ICH). Tenecteplase (TNKase, Genetech Inc.) is an engineered variant of alteplase (Activase, Genentech Inc.) designed to have increased fibrin specificity, greater efficacy and a longer half-life. The longer half-life of tenecteplase compared to alteplase allows for convenient single bolus administration of the drug. In addition, tenecteplase dosing is based on actual or estimated patient weight, which enhances both the safety and efficacy outcomes. Large clinical trials have demonstrated equivalence in mortality and ICH between tenecteplase and alteplase. Compared to alteplase, tenecteplase use leads to lower rates of bleeding complications and a decreased risk of ICH among low weight, elderly women.     

Tenecteplase: new preparation. Another thrombolytic agent for myocardial infarction: a slightly simpler treatment

(1) Alteplase is the standard thrombolytic agent for treating patients under 75 years with myocardial infarction if they are seen within 6 hours. It is given as an intravenous infusion over 90 minutes in combination with aspirin and unfractionated or low-molecular-weight heparin. (2) Tenecteplase has been authorized for use in myocardial infarction as an intravenous bolus over 5 to 10 seconds. (3) The evaluation file on tenecteplase contains data from three dose-finding studies and one double-blind trial against alteplase in nearly 17 000 patients. The trial found no difference in mortality between the two treatments (6% at 30 days). Nor was there any substantial difference in serious adverse events (stroke, intracranial haemorrhage or heart failure). (4) Major haemorrhage was slightly less frequent in patients given tenecteplase, but there was no difference between groups in the incidence of intracranial haemorrhage or stroke. (5) A comparative trial suffering from a number of biases suggests that combined treatment with tenecteplase + enoxaparin has a similar risk-benefit ratio to combined treatment with tenecteplase + unfractionated heparin. The combination of tenecteplase and enoxaparin makes treatment simpler, which could be particularly useful prior to hospital admission. A smaller trial of alteplase + enoxaparin against alteplase + unfractionated heparin gave similar findings. (6) In practice, tenecteplase has the advantage of a more convenient administration; a very large trial strongly suggests that its effects are almost identical to those of alteplase.     

Comparison of pharmacokinetics of lanoteplase and alteplase during acute myocardial infarction

OBJECTIVE: Lanoteplase is a rationally designed variant of tissue plasminogen activator. The aim of this study was to examine the pharmacokinetics and functional activity of a single intravenous bolus dose of lanoteplase with those of a bolus plus two-step infusion of alteplase. DESIGN: Seven-centre substudy of the InTIME-I angiographic trial in patients presenting within 6 hours of onset of suspected acute myocardial infarction. PATIENTS AND PARTICIPANTS: A total of 31 patients (28 males, 3 females) enrolled in this substudy [mean age 59 (range 26 to 76) years]. METHODS: Twenty-three patients randomised to lanoteplase received single bolus doses of 15 kU/kg (n = 5), 30 kU/kg (n = 3), 60 kU/kg (n = 9), or 120 kU/kg (n = 6). Eight patients received alteplase 相似文献   

Meprobamate kinetics during and after terminated hemoperfusion in acute intoxications

We report four cases of severe meprobamate intoxication. Maximal plasma levels reached 800 (176), 816 (180), 863 (190) and 923 mumol/l (203 mg/l). All patients survived without sequelae including one patient resuscitated from cardiac arrest. The clinical course was complicated by coma, hypotension, and hypothermia in all patients. Three cases were treated with charcoal hemoperfusion with mean hemoperfusion clearance ranging from 134-164 ml/min compared to 174 ml/min in one case treated with resin filter and the same blood flow of 200 ml/min. In two cases, a mean renal meprobamate clearance of 15 and 23 ml/min was calculated comprising only 9-15% of the hemoperfusion clearance. The amount of meprobamate removed by hemoperfusion ranged from 1.6-6.2 g. In one case, the half-life of plasma meprobamate during hemoperfusion was 2.6 hours compared to 8.3 hours after hemoperfusion. Thus the half-life was reduced more than 3-fold. These data show that hemoperfusion may be indicated in severe meprobamate intoxication.     

Coronary thrombolytic properties of a novel recombinant plasminogen activator (BM 06.022) in a canine model.

We studied the thrombolytic dose-response relationship of a recombinant plasminogen activator (rPA) (BM 06.022) compared with alteplase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle 2 and protease domains of human tissue PA (tPA) and lacks oligosaccharide side chains because of its expression in Escherichia coli. Thrombus formation in anesthetized, open-chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery in the presence of a critical stenosis. Intravenous bolus injection of BM 06.022 (50, 100, 140, and 200 kU/kg) or of alteplase (200, 800, 1,130, and 1,600 kU/kg) 30 min after coronary occlusion to six heparinized dogs per group achieved a dose-dependent increase in reperfusion rate and decrease in residual thrombus wet weight. Vehicle-treated dogs did not reperfuse. Semilogarithmic regression analysis showed that the effective dose that produced 50% reperfusion of BM 06.022 (83 kU/kg) was 11.6-fold lower than that of alteplase (951 kU/kg). Comparison with infusion experiments showed that intravenous bolus injection of 140 kU/kg of BM 06.022 was equieffective to a 90-min infusion of 800 kU/kg (= 1 mg/kg) of alteplase as a standard treatment regarding reperfusion rate (66%) and time to reperfusion (15 +/- 6 vs. 18 +/- 8 min). Pharmacokinetic analysis for functionally active BM 06.022 or alteplase in plasma revealed a total plasma clearance of 4.1-6.6 ml/min/kg for BM 06.022 and of 12.6-42.3 ml/min/kg for alteplase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma concentrations of isosorbide dinitrate after oral administration of a sustained-release formulation to human subjects

1. A peak of mean plasma concentrations of isosorbide dinitrate of 5.8 ng/ml was reached at 0.5 h after a single oral dose of 5 mg in a standard tablet formulation. Thereafter mean concentrations declined with a half-life of about 48 min. 2. A peak of mean concentrations of isosorbide dinitrate of 3.2 ng/ml was reached at 2--4 h after a single oral dose of 20mg in a sustained-realease capsule formulation (Iso Mack Retard). Thereafter mean concentrations declined by about twofold during 6 h and were still detectable at 12 h after dosing. 3. When corrected by dose/bodyweight variations, the mean area under the isosorbide dinitrate plasma concentration curve from the sustained-release capule was 76% of that from the standard tablet and this formulation-related difference in bioavailability was statistically significant (p less than 0.05). 4. The results showed that sustained-release formulation is a useful way to maintain plasma concentrations of isosorbide dinitrate for several hours.     

Biopharmaceutics and metabolism of yohimbine in humans.

The biopharmaceutics of yohimbine (YO) and the pharmacokinetics of 10-hydroxy-yohimbine (10-OH-YO) and 11-hydroxy-yohimbine (11-OH-YO) were investigated in healthy subjects following i.v. (5 mg) and oral (8 mg) dosing. One subject was found as a slow hydroxylator of YO. The mean (+/-S.D.) oral absolute bioavailability of YO was 22.3+/-21. 5%. Total plasma clearance (CL) and renal clearance (CL(r)) of YO following i.v. dosing were 0.728+/-0.256 ml/min and 0.001+/-0.002 ml/min, respectively. Based on the steady-state volume of distribution (V(ss)), YO had a relatively low distribution (V(ss) = 32.2+/-12.1 l). The overall renal excretion of YO, 10-OH-YO and 11-OH-YO, expressed as percent of the dose of YO administered, were not different following i.v. and oral dosing, and were around 0.1, 0.2 and 14%, respectively. Following i.v. dosing of YO, the mean apparent terminal half-life of 11-OH-YO (347+/-63 min) was almost four times higher than that of YO (91.0+/-33.6 min) suggesting an elimination rate-limited kinetics for 11-OH-YO.     

Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose

AIMS: 1) To develop an estimate of oral clearance (CL(Px)/F) for the antianginal agent perhexiline based on the ratio of cis-OH-perhexiline metabolite/parent perhexiline plasma concentrations at steady-state (C(OHPx,ss)/C(Px,ss)). 2) To determine whether the ratio measured in the first fortnight of treatment (C(i)(OHPx)/C(i)(Px)) may be used to guide patient dosing with perhexiline, a drug with a narrow therapeutic index, long half-life and saturable metabolism via CYP2D6. METHODS: Two retrospective studies were conducted reviewing patient records and data obtained from routine monitoring of plasma perhexiline and cis-OH-perhexiline concentrations. RESULTS: Study 1 (n=70). At steady-state, the frequency distributions of CL(Px)/F and C(OHPx,ss)/C(Px,ss) were consistent with CYP2D6 metabolism. Putative poor metabolizers (approximately 8%) were identified by CL(Px)/F< or =50 ml min(-1) or C(OHPx,ss)/C(Px,ss)< or =0.3. A group of patients with CL(Px)/F> or =950 ml min(-1) may have been ultra-rapid metabolizers. In this group, the high CL(Px)/F values suggest extensive first-pass metabolism and poor bioavailability. In patients with therapeutic plasma perhexiline concentrations (0.15-0.60 mg l(-1)), the variability in dose appeared directly proportional to CL(Px)/F (r2=0.741, P<0.0001). Study 2 (n=23). Using C(i)(OHPx)/C(i)(Px) patients were tentatively identified as poor, extensive and ultra-rapid metabolizers, with CL(Px)/F of 23-72, 134-868 and 947-1462 ml min(-1), respectively, requiring doses of 10-25, 100-250 and 300-500 mg day(-1), respectively. CONCLUSIONS: The cis-OH-perhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.     

Ranitidine: single dose pharmacokinetics and absolute bioavailability in man

1 Ranitidine single dose pharmacokinetics and absolute bioavailability have been studied in five healthy male volunteers. Following an overnight fast, 150 mg was given intravenously as a bolus injection or orally as a tablet formulation to each subject on separate occasions. 2 Following intravenous administration, plasma levels declined biexponentially. The mean (+/- s.d.) distribution half-life (t 1/2 alpha) was 6.6 +/- 1.6 min; plasma half-life (t 1/2 beta) was 1.7 +/- 0.2 h; the volume of distribution (V) was 96 +/- 9 1; total body clearance (CL) was 647 +/- 94 ml/min and renal clearance (CLR) 520 +/- 123 ml/min. 3 Following oral administration plasma levels showed a bimodal pattern with a first peak at 1.1 +/- 0.4 h and a second peak at 3 +/- 0 h. The absolute availability was 60 +/- 17%. The plasma half-life (t 1/2) of 2.3 +/- 0.4 h was significantly longer (P less than 0.05) after oral than after i.v. administration. 4 Renal excretion of unchanged ranitidine accounted for 79 +/- 9% of the dose after i.v. administration and for 27 +/- 7% after oral administration. 5 Our results suggest a more extensive biotransformation of ranitidine and biliary excretion of metabolites after oral administration while i.v. administration ranitidine is preferentially excreted unchanged in the urine.     

Effects of long-term grapefruit juice ingestion on nifedipine pharmacokinetics: induction of rat hepatic P-450 by grapefruit juice.

We studied the effects of short- and long-term ingestion of grapefruit juice (GJ) on nifedipine (NFP) pharmacokinetics in rats. Thirty minutes after intraduodenal (id) administration of 2.0 ml of GJ or saline, NFP was i.v. or id administered at a dose of 3 mg/kg b. wt. No significant differences were observed in pharmacokinetic values between the two groups after i.v. administrations of NFP. By contrast, after id administration, the mean AUC value in the GJ group was approximately 1.62 times that in the control group, and the mean apparent clearance (CL) decreased by approximately 40%. In addition, 2.0 ml of GJ was orally administered twice a day (9:00 AM and 7:00 PM) for 10 consecutive days; on the 11th day the pharmacokinetics of NFP were examined again. Irrespective of route of administration (i.v. or id), NFP CL from plasma in these GJ-treated rats was considerably faster than that in the rats treated with GJ for a short (30-min) period. In microsomes prepared from the intestinal mucosa of animals receiving long-term administration of GJ, NFP oxidation activity (0.21 +/- 0.02 nmol/mg/min) and P-450 content (0.045 +/- 0.009 nmol/mg) were significantly lower than those in untreated rats (0.32 +/- 0.05 nmol/mg/min and 0.060 +/- 0.007 nmol/mg). In hepatic microsomes from the same rats, however, NFP oxidation activity (1.43 +/- 0.17 nmol/mg/min) and P-450 content (0.66 +/- 0.07 nmol/mg) were distinctly greater than those in untreated rats (1.00 +/- 0.06 nmol/mg/min and 0.51 +/- 0.04 nmol/mg). In conclusion, short-term id exposure to GJ resulted in increased NFP bioavailability, whereas long-term administration of GJ resulted in reduced bioavailability and increased CL.     

Toxicokinetics of bromodichloroacetate in B6C3F1 mice

The oral and i.v. elimination kinetics were investigated for bromodichloroacetate (BDCA), a haloacetate found in drinking water. The BDCA was administered at a dose of 5, 20 and 100 mg kg-1 to B6C3F1 mice and appears to distribute to the total body water with a mean volume of distribution of 427 +/- 79 ml kg-1. It is subject to first-pass hepatic metabolism with a range of bioavailabilities of 0.28-0.73. A mean terminal half-life of 1.37 +/- 0.21 h. was calculated from the two lower doses of both i.v. and oral administration. Non-linear behavior was exhibited at doses greater than 20 mg kg-1, with a much higher than expected area under the curve (AUC), a decrease in total body clearance (CL(b)) and an increase in the terminal half-life to 2.3 h at the highest dose. The average CL(b) was 220 ml h(-1) kg-1 for the lower two doses but decreased to 156 ml h(-1) kg-1 at the high dose. The BDCA is primarily eliminated by metabolism, with only 2.4% of the parent dose being recovered in the urine at the high dose. The unbound renal clearance, as calculated from the high dose, was 15.0 ml h(-1) kg-1. The BDCA is moderately bound to plasma proteins (f(u) = 0.28) and preferentially distributes to the plasma with a blood/plasma ratio of 0.88.     

Fundamental and clinical studies of cefotiam in neonates and premature infants

Single doses of cefotiam (CTM) by bolus injection of 20 mg/kg of CTM were given to 17 neonates and premature babies (11 prematures) and plasma and urine CTM levels as well as urinary recovery rates of CTM were determined. The CTM was also evaluated clinically with regard to therapeutic and protective effects, bacteriological efficacy as well as safety. A mean daily dose of 56.6 mg/kg of CTM was given intravenously in 2 to 4 divided doses for an average of 8 days to 11 neonates and prematures consisting of 1 case with pneumonia, 2 suspected septicemia, 3 urinary tract infections and 5 for prophylaxis against infections. (In the 6 babies evaluated for clinical effects, a mean dose of 59.8 mg/kg/day of CTM was given for an average 9 days). The findings of these studies are summarized below: The mean peak plasma level of 2 cases of 4-7 day-old neonates was 32.3 mcg/ml 5 minutes after injection. The mean AUC was 96.6 mcg X hr/ml, and the mean half-life was 2.12 hours. In 3 of the 4 neonates of 8-14 day-old group, the mean peak plasma level of 55.6 mcg/ml was obtained after 5 minutes. The mean AUC was 63.0 mcg X hr/ml and the mean half-life was 0.82 hour. Compared to the 4-7 day-old group, AUC was smaller and half-life was shorter in this group. In premature infants, plasma CTM levels were determined in 2, 1, 1, 5 and 2 cases of the 0-3, 4-7, 8-14, 15-21 and 22-28 day-old infants, respectively. In the 8-14 day-old group and one of 15-21 day-old group, peak plasma levels were obtained after 15 minutes. Peak plasma levels in the remaining groups, were attained after 5 minutes. Peak plasma levels in the 5 groups were 40.7, 48.4, 33.9, 38.1 and 45.3 mcg/ml, respectively. Mean or individual AUC's obtained after excluding markedly varying values from the respective groups were 122.0, 96.2, 65.2, 72.8 and 60.4 mcg X hr/ml, respectively. With the increasing age, the AUC tended to decrease. Mean or individual half-lives were 2.31, 1.47, 1.28, 1.41 and 0.96 hours, respectively, showing a tendency to decrease with increasing age. In 6 neonates, high urinary levels continued up to 6 hours after administration. Mean 6-hour urine recoveries in the 4-7 and 8-14 day-old groups were 16.6% and 43.0%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Novel thrombolytic drugs: will they make a difference in the treatment of ischaemic stroke?

Treatment of acute ischaemic stroke aims to recanalize the occluded artery, salvage the at-risk brain tissue and thus minimize neurological sequelae. Efforts a decade ago have led to the only currently approved medical treatment for acute ischaemic stroke, i.e. intravenous alteplase given within 3 hours of stroke onset. Recanalization occurs in only one-half of the patients receiving alteplase, and only approximately 5% of all ischaemic stroke patients in industrialized countries receive this treatment. Studies are currently being carried out to determine whether intravenous alteplase would be safe and effective for up to 4.5 hours after ischaemic stroke onset, and whether it should be followed by an intra-arterial approach. Two novel thrombolytic drugs being studied for acute ischaemic stroke are desmoteplase and tenecteplase. Although the first trials were promising, the most recent evidence suggests that desmoteplase is not superior to placebo, even in carefully selected patients, in the 3- to 9-hour time window after stroke onset. Tenecteplase has only been studied for acute ischaemic stroke in a single noncontrolled, dose-finding trial in the 3-hour time window after stroke onset, which suggested a similar efficacy to that demonstrated in the historical data from the alteplase trials. A trial to compare the safety and efficacy of tenecteplase versus alteplase is ongoing. Safer and more effective thrombolytic drugs for the treatment of ischaemic stroke are thus being sought. Such agents will be welcome, but they are not here yet. While waiting we are likely to see the emergence of additive therapies, including ultrasound insonation, neuroprotective/regenerative agents and invasive intra-arterial techniques. Novel thrombolytic drugs, or other novel therapies, possess great potential to make a difference in the future, but the most urgent priority now is in the organization of stroke treatment in such a way that more patients receive the currently available optimal treatments.     

Preclinical disposition of GDC-0973 and prospective and retrospective analysis of human dose and efficacy predictions

[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone (GDC-0973) is a potent and highly selective inhibitor of mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase (ERK) 1/2 (MEK1/2), a MAPK kinase that activates ERK1/2. The objectives of these studies were to characterize the disposition of GDC-0973 in preclinical species and to determine the relationship of GDC-0973 plasma concentrations to efficacy in Colo205 mouse xenograft models. The clearance (CL) of GDC-0973 was moderate in mouse (33.5 ml · min(-1) · kg(-1)), rat (37.9 ± 7.2 ml · min(-1) · kg(-1)), and monkey (29.6 ± 8.5 ml · min(-1) · kg(-1)). CL in dog was low (5.5 ± 0.3 ml · min(-1) · kg(-1)). The volume of distribution across species was large, 6-fold to 15-fold body water; half-lives ranged from 4 to 13 h. Protein binding in mouse, rat, dog, monkey, and human was high, with percentage unbound, 1 to 6%. GDC-0973-related radioactivity was rapidly and extensively distributed to tissues; however, low concentrations were observed in the brain. In rats and dogs, [(14)C]GDC-0973 was well absorbed (fraction absorbed, 70-80%). The majority of [(14)C]GDC-0973-related radioactivity was recovered in the bile of rat (74-81%) and dog (65%). The CL and volume of distribution of GDC-0973 in human, predicted by allometry, was 2.9 ml · min(-1) · kg(-1) and 9.9 l/kg, respectively. The predicted half-life was 39 h. To characterize the relationship between plasma concentration of GDC-0973 and tumor growth inhibition, pharmacokinetic-pharmacodynamic modeling was applied using an indirect response model. The KC(50) value for tumor growth inhibition in Colo205 xenografts was estimated to be 0.389 μM, and the predicted clinical efficacious dose was ～10 mg. Taken together, these data are useful in assessing the disposition of GDC-0973, and where available, comparisons with human data were made.     

Pharmacokinetics of 4-hydroxycyclophosphamide and metabolites in the rat.

Pharmacokinetics of 4-hydroxycyclophosphamide (4-OHCP), the major active microsomal metabolite of cyclophosphamide (CP), were investigated in the Sprague-Dawley rat following separate iv bolus administrations of CP, synthetic 4-OHCP, and their combination. CP, 4-OHCP, and other metabolites such as phosphoramide mustard, alcophosphamide, and 3-(2-chloroethyl)-1,3-oxazolidin-2-one in rat plasma were simultaneously analyzed using GC/MS and stable isotope dilution techniques. Following iv administrations of 4-OHCP to rats at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg, phosphoramide mustard was found to be the major circulating metabolite followed by alcophosphamide and 3-(2-chloroethyl)-1,3-oxazolidin-2-one. No appreciable amount of nor-nitrogen mustard was detected in circulation. The mean excretion of unchanged 4-OHCP in two rats was 4.1 +/- 0.2% of the administered dose in 24-hr urine. Plasma concentration-time profiles of 4-OHCP declined monoexponentially with a mean half-life and total plasma clearance values of 8.1 min and 81.2 ml/min.kg, respectively. No dose-dependent kinetics were apparent between the 10 and 40 mg/kg doses used. The short half-life of 4-OHCP may be due partly to its degradation in plasma, which was found to be a first-order process in vitro with a half-life of 5.2 min. On the other hand, when CP was administrated to eight separate rats at 20 mg/kg each, the mean apparent elimination half-life for the derived 4-OHCP was 55.4 min as compared to 58.2 min, the mean elimination half-life for the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phenotyping CYP3A using midazolam in cancer and noncancer Asian patients

AIMS: To investigate CYP3A activity in cancer and noncancer Asian patients using midazolam and to reveal possible alternative traits for phenotyping CYP3A. METHODS: Intravenous midazolam 2.5 mg or 2.5-8 mg was administered to 27 cancer and 24 noncancer patients, respectively. Plasma was sampled at 0, 0.25, 0.5, 1, 1.5, 2, 3.5 and 5 h after intravenous ultrashort, 30 s infusion. Plasma midazolam and 1'-hydroxymidazolam concentrations were determined using GCMS. The disposition of midazolam and 1'-hydroxymidazolam in these patients was compared. Midazolam clearance was correlated with dose-normalized plasma midazolam concentrations (concentration/per dose). RESULTS: Clearance (CL) and steady state volume of distribution (Vss) of midazolam (mean +/- SD, 95% confidence level) in cancer (424 +/- 155, 61.3 ml min(-1); 1.21 +/- 0.46, 0.18 l kg(-1)) and noncancer (407 +/- 135, 57.1 ml min(-1); 1.15 +/- 0.33, 0.155 l kg(-1)) patients, respectively, were not different and comparable with published data. Clearance variability was 4-5 fold in both groups. Midazolam clearance correlated significantly with all plasma concentration/per dose at and after the 1-h time point, with a minimum correlation coefficient of r = 0.752, P < 0.001. CONCLUSIONS: CYP3A activities determined with different doses of midazolam in cancer and noncancer Asian patients showed variability of 4-5-fold and were not different between groups. One to two-fold plasma midazolam concentrations per dose may be feasible as a simple alternative phenotypic trait for hepatic CYP3A activity determination.