Parent Drug In Plasma Research Articles

Prodrugs of the cancer cell selective anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) are orally efficacious in a mouse model of resistant colon cancer

A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.

The metabolites of Ambinine, a benzo[c]phenanthridine alkaloid, in rats identified by ultra-performance liquid chromatography-quadrupoletime-of-flight mass spectrometry (UPLC/Q-TOF-MS/MS).

Ambinine (AM), one of the major hexahydrobenzo[c]phenanthridine alkaloids from Corydalis ambigua Cham. et Schlecht. var. amurensis Maxim, is considered to be an important compound because of its special content and activity. However, there are few published studies on AM metabolism. In this research, the metabolism of AM in vivo was comprehensively studied for the first time. A total 44 metabolites (including 13 phase I and 31 phase II metabolites) as well as its parent drug in plasma, bile, urine and feces of rats were identified and 41 of them were reported for the first time. The results obtained indicated that demethylation, sulfation and glucuronidation were the major metabolic pathways of AM in vivo. Furthermore, this study provides valuable and new information about the metabolism of AM, which will be very helpful for understanding the safety and efficacy of AM, as well as its analogues.

Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

Phase 0 studies can provide initial pharmacokinetics (PKs) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of 2 antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. We administered a microdose (100 μg) of C-labeled drug (ZDV or tenofovir disoproxil fumarate) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and CD4 cells were measured by accelerator mass spectrometry. The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg-300 mg), whereas the intracellular TFV-DP PKs were linear over the same dose range. ZDV-TP concentrations were lower in CD4 cells versus total PBMCs, whereas TFV-DP concentrations were not different in CD4 cells and PBMCs. Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. Accelerator mass spectrometry shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs.

Mevalonate independent effects of atorvastatin on angiogenesis: Relevance to cancer

Abstract Much uncertainty remains about statins effects on cancer and regardless of their widespread benefits we should be cautious about them. A growing body of preclinical data indicates that statins may have antineoplastic properties, but some studies raise the possibility that statins may possess a carcinogenic potential. Our preliminary experimental study in a rat air pouch model of local inflammation showed that oral administration of atorvastatin can inhibit angiogenesis, however, surprisingly its local injection into the pouch resulted in significant pro-angiogenic effects. Contrary to pro-angiogenic effect of locally administrated drug, the antiangiogenic effect of oral atorvastatin was prevented by mevalonate. We also witnessed that the high doses of atorvastatin, as a potent and long-acting statin, augmented croton oil induced skin tumors in mice. Thus, upon these findings, occurrence of extra hepatic and the direct effects of potent and long-acting statins through producing sufficient amount of the parent drug in plasma can be hypothesized, as a result of which potentially undesirable inadvertent impacts can occur in patients who receive potent and extensive acting statins for a long period of time.

Mevalonate independent effects of atorvastatin on angiogenesis: Relevance to cancer

Much uncertainty remains about statins effects on cancer and regardless of their widespread benefits we should be cautious about them. A growing body of preclinical data indicates that statins may have antineoplastic properties, but some studies raise the possibility that statins may possess a carcinogenic potential. Our preliminary experimental study in a rat air pouch model of local inflammation showed that oral administration of atorvastatin can inhibit angiogenesis, however, surprisingly its local injection into the pouch resulted in significant pro-angiogenic effects. Contrary to pro-angiogenic effect of locally administrated drug, the antiangiogenic effect of oral atorvastatin was prevented by mevalonate. We also witnessed that the high doses of atorvastatin, as a potent and long-acting statin, augmented croton oil induced skin tumors in mice. Thus, upon these findings, occurrence of extra hepatic and the direct effects of potent and long-acting statins through producing sufficient amount of the parent drug in plasma can be hypothesized, as a result of which potentially undesirable inadvertent impacts can occur in patients who receive potent and extensive acting statins for a long period of time.

Disposition of liposomal daunorubicin during cotreatment with cytarabine in patients with leukaemia.

To investigate the pharmacokinetics and pharmacodynamics of liposomal daunorubicin (DaunoXome) 80 or 100 mg/m(2) on days 1, 2 and 3 coadministered with standard or high-dose cytarabine to patients with poor-risk acute leukaemia. Unblinded pharmacokinetic-pharmacodynamic study. Twenty-three adult patients with acute leukaemia. Blood, bone marrow and urine samples were collected at appropriate intervals on days 1-6. Total daunorubicin and daunorubicinol concentrations in plasma, bone marrow, peripheral blood cells and urine were measured by high performance liquid chromatography. Liposomal daunorubicin exhibited a markedly different pharmacokinetic behaviour from the free drug due to a slow distribution of the liposomal moiety into the body. The ratio of area under the concentration-time curve (AUC) for metabolite to parent drug was lower for liposomal daunorubicin than for free daunorubicin, mainly due to higher concentrations of the parent drug in plasma, whereas daunorubicinol exposure was more or less comparable, if not higher. After liposomal daunorubicin at both 80 and 100 mg/m(2), total daunorubicin concentrations in leukaemic cells were at least similar to those observed for free daunorubicin, and significant accumulation was also observed in bone marrow blast cells. Nineteen of 23 patients obtained a complete remission, although 13 had P-glycoprotein-overexpressing blast cells. Grade 3-4 mucositis was found only in three patients with very high AUCs for total daunorubicin and daunorubicinol. Liposomal daunorubicin at both 80 and 100 mg/m(2) in combination with cytarabine may represent a valid treatment for high-risk acute leukaemia. Liposomal daunorubicin may be helpful in overcoming multidrug resistance, since it shows significant accumulation into tumour target cells, irrespective of P-glycoprotein expression. The tolerability profile suggests that toxicity may be related to exposure to both the parent drug and the metabolite.

Zatebradine: Pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects

AbstractZatebradine (1; UL-FS 49 CL; 1, 3, 4, 5-[tetrahydro-7, 8-dimethoxy-3-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]methylamino]propyl]-2H-3-benzazepin-2-on-hydrochloride)] is the proposed INN name for a nonchiral, novel, specific heart-rate-lowering drug that is suitable for the treatment of stable angina pectoris. The pharmacokinetics of 1 and of total radioactivity in healthy volunteers (n = 6) were determined after intravenous infusion and oral administration of an experimental drug solution containing 7.5mg (1.85MBq) of 14C-labeled drug. Concentrations in plasma and urine were measured by a specific, sensitive, reversed-phase automated high-performance liquid chromatography system with fluorimetric detection at 285nm Ex, 315nm Em and by liquid scintillation counting. Recovery of total radioactivity was 89.8 ± 2.3% (infusion) and 92.2 ± 3.0% (oral). Renal elimination of total radioactivity was 62.5 ± 2.0% (infusion) and 48.8 ± 3.1% (oral). After intravenous infusion and oral administration, 27.3 ± 2.4 and 43.4 ± 3.9%, respectively, of the administered dose was eliminated in the feces. Absorption, based on renal excretion of total radioactivity following oral and intravenous dosing, was 79.2 ± 15.3% (mean ± standard deviation). Unchanged parent drug contributed 28.4 ± 5.8% (infusion) and 12.4 ± 3.7% (oral) of the dose to renal excretion. Zero to three minutes after cessation of the 20-min infusion, the maximum concentration of parent drug in plasma was 161.9 ± 70.9ng/mL. After oral administration, a mean peak concentration in plasma of 24.3 ± 6.7ng/mL (0.5-3h postadministration) was reached. Data regarding levels of 1 in plasma could be adequately fitted with an open, two-compartment model. The dominant terminal half-life (infusion) of 1 was 2.80 ± 0.8h (range 1.82–3.40h). Mean residence times were 3.2 ± 0.8h (infusion) and 4.6 ± 0.8h (oral administration), and total body clearances were 630 ± 243mL/min (infusion) and 1197 ± 538mL/min (oral). Absolute bioavailability was 51.5 ± 17.8% (range 29.0–80.0%) based on data from the area under the curve of concentration in plasma versus time and 45.0 ± 17.0% (range 30.0–70.0%) based on renal excretion of parent drug.

Determination of cyclosporine in plasma: specific radioimmunoassay with a monoclonal antibody and liquid chromatography compared.

A radioimmunoassay of cyclosporine (Sandimmune) involving use of a mouse monoclonal antibody was tested to monitor specifically the parent drug in plasma. The cyclosporine concentrations obtained by RIA were compared with those obtained by the HPLC method. For the RIA method, the within- and between-assay CVs are less than 6%, the limit of detection is about 10 micrograms/L for a 50-microL sample of plasma. For the HPLC method, the within- and between-assay CVs are less than 20%, the limit of detection is about 15 micrograms/L for a 1-mL sample of plasma. The concentrations by RIA correlated well with those by HPLC in samples from patients receiving bone-marrow (n = 39), heart (n = 52), or liver (n = 51) transplants. In all indications, the ratio of values by RIA to those by HPLC for these samples remained stable and close to 1 during the drug-monitoring period, i.e., for up to 202 days. Therefore, the specific RIA can be used instead of HPLC to measure the parent drug in plasma.

Comparative pharmacokinetics and cardiovascular effects of tiapamil in healthy volunteers and patients with hepatic cirrhosis.

Tiapamil 70 mg was administered i.v. to 8 healthy male volunteers and 8 patients (7 males, 1 female) with biopsy proven hepatic cirrhosis. Two of the patients also received 600 mg p.o. Serial plasma and urine samples were collected and the parent drug in plasma and urine and desmethyl-tiapamil in urine were assayed by a specific HPLC method. The plasma and urine data for the parent drug after i.v. and p.o. dosing were simultaneously fitted to linear p.o. and i.v. two compartment models with exit from and input into the central compartment. Absorption was assumed to be a first order process. In the volunteers the mean pharmacokinetic parameters were: 101 l for the steady-state volume of distribution 750 ml X min-1 for nonrenal clearance, 195 ml X min-1 for renal clearance and 1.7 h for the half-life of the terminal disposition phase. The urinary recoveries of the parent drug and desmethyltiapamil averaged 21.4 and 0.8% of the dose, respectively. In the patients the steady-state volume of distribution, the amount of unchanged drug in urine and the half-life of the terminal disposition phase were significantly increased (171 l, 29.0% of the dose, 3.5 h, respectively). Decreased plasma protein binding in the patients accounted for the larger steady-state volume of distribution. The nonrenal clearance of 519 ml X min-1, tended to be smaller in the patients than in the volunteers. Together with the increased urinary recovery of tiapamil in the patients this indicates a moderately impaired elimination capacity in the cirrhotics.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of food and of antacid on the single oral dose pharmacokinetics of tenoxicam.

A single oral dose (40 mg) of tenoxicam (Ro12-0068) was administered to six normal male volunteers pre- and post-prandially and to a further six volunteers with and without antacid to determine the effect of food and and of antacid on absorption. The rate of absorption was slower with post-prandial than with pre-prandial administration, resulting in a significantly later time for peak plasma drug levels (4.1 h compared to 1.3 h). No effect was evident on the extent of absorption or other pharmacokinetic parameters. Similarly, the rate of absorption was significantly slower after concurrent antacid than without antacid (t1/2 0.47 h compared to 0.18 h) resulting in a later peak time (4.7 h compared to 2.3 h) and significantly lower peak level (4.2 micrograms X ml-1 compared to 5.1 micrograms X ml-1) of parent drug in plasma. Again, no effect was evident on the extent of absorption or other pharmacokinetic parameters. It is concluded that food and antacids both tend to reduce the rate of absorption of tenoxicam, but that the extent of absorption is essentially unchanged. The influence on the overall kinetic profile is relatively minor, and thus unlikely to affect the therapeutic response.

Pharmacokinetics of vinpocetine and its metabolite, apovincaminic acid, in plasma and cerebrospinal fluid after intravenous infusion

The pharmacokinetics of vinpocetine (ethyl apovincaminate, Cavinton) and its metabolite, apovincaminic acid, was studied in patients with cerebrovascular disorders. Vinpocetine (1 mg/kg) was infused intravenously over 25 min. The elimination half-life of the parent drug in plasma was 4.7+/-2.13 h. Total clearance of vinpocetine was 0.79+/-0.1 1 h(-1) kg(-1). The presence of vinpocetine in cerebrospinal fluid shows that the drug is able to pass through the blood-brain barrier and reach the central nervous system which is a possible site of action. The maximum increase of cerebral blood flow (25%) was measured at 32 min after the start of the infusion.

Some pitfalls in selecting descriptive pharmacokinetic models.

Some pitfalls in selecting pharmacokinetic models are enumerated. To calculate the pharmacokinetic parameters of a drug that exhibits a biphasic convex plasma concentration-time curve, a two-compartment model does not automatically have to be applied. When only the parent drug in plasma is considered, a two-compartment model seems to be most appropriate. However, when the kinetic behavior of the metabolite has to be taken into account, and when a metabolic equilibrium underlies the metabolic elimination, the two-compartment model may not be appropriate. Also, when calculating the kinetic parameters of a drug with a concave biphasic plasma concentration-time curve, a capacity-limited metabolic conversion is not the automatic explanation for this observation. Limitations in renal excretion and bioavailability may be the reasons for this behavior. Convex and concave biphasic plasma concentration-time curves are illustrated, using sulfonamides as test compounds.

Bromperidol Radioimmunoassay: Human Plasma Levels

A sensitive radioimmunoassay (RIA) procedure was developed to assay for bromperidol levels in human plasma after therapeutic drug administration. The antisera used in the RIA procedure was generated in rabbits against a haloperidol-bovine serum albumin conjugate. Tritiated haloperidol was used as the radioligand in the assay. A single ether extraction of alkalinized plasma was used to separate bromperidol from its more polar metabolites and to reduce assay variability encountered with a direct plasma assay. The lower limit of detection was ~0.5 ng/mL of parent drug in plasma. The assay exhibited within- and between-assay variabilities of ~9 and 14%, respectively. A 103–106% recovery of bromperidol from quality control plasma samples was observed over the concentration range of 1–150 ng/mL. A correlation coefficient of 0.9999 with respect to measured versus expected bromperidol content in the quality control plasma samples was exhibited. Cross-reactivity characteristics of the antisera indicated that dehydrobromperidol could significantly interfere (~25% cross-reactivity) with the RIA procedure. However, biotransformation studies have not suggested this compound as a metabolite of bromperidol. Predose (Cmin) plasma levels of bromperidol in schizophrenic patients maintained on drug therapy are also reported.

Disposition and metabolism of a new benzothiophene antiestrogen in rats, dogs and monkeys.

A new benzothiophene-derived antiestrogen (LY156758) when orally administered was well absorbed in rats and monkeys while approx. 20% was absorbed in dogs. In the rat the compound was subject to first-pass hepatic metabolism which led to low levels of parent drug in the systematic circulation together with a small amount as the glucuronide conjugate. In monkeys the compound occurred primarily as the glucuronide conjugate of parent drug with very little circulating free drug. The systemic bioavailability of free parent drug in plasma was 39% in rats, 17% in dogs and 5% in monkeys. Excretion of the drug in rats and dogs was primarily via the bile. Approx. 1% of the dose was excreted in the urine of rats and dogs after oral dosing. In rats, at least 50% of an oral dose was excreted in bile as the glucuronide conjugate of parent drug.

The fate of [14C]trithiozine in man.

1. Radioactivity of [14C]trithiozine (4-(3,4,5-trimethoxythiobenzoyl)tetrahydro-1,4-oxazine) was recovered quantitatively in the excreta within four days of a single dose (400 mg) given to four human subjects. The urine was the major route of elimination. 2. The concn. of parent drug in plasma showed a peak at 1 X 5 h after dosing and a half-life 7 h. Two metabolites were detected in plasma, corresponding to the products of desulphuration and demethylation. 3. Little unchanged drug was excreted in urine (0 X 9%). Major pathways of metabolism were O-demethylation at the 3 or 4 positions of the benzene ring followed by conjugation, S-oxidation to the sulphoxide, and desulphuration of the thiobenzoyl group to form the benzoyl analogue. The trimethoxybenzoyl metabolite underwent O-demethylation at the 3 or 4 position of the benzene ring following by conjugation, mono- and di-hydroxylation of the heterocyclic ring and scission of the heterocyclic ring to yield both neutral and acid metabolites.