Metabolism and murine pharmacokinetics of the 8-(N,N-dimethylcarboxamide) analogue of the experimental antitumor drug mitozolomide (NSC353451).

The in vitro cytotoxicity, stability, and metabolism of the 8-(N,N-dimethylcarboxamide) and 8-(N-methylcarboxamide) analogues of the experimental antitumor drug mitozolomide have been investigated in conjunction with their in vivo murine pharmacokinetics and metabolism. When tested against the TLX5 lymphoma in vitro the ID50 values for dimethylmitozolomide, methylmitozolomide, and mitozolomide were 14.6, 3.0, and 2.3 microM, respectively. The cytotoxicity of dimethylmitozolomide was dramatically increased when it was incubated with murine hepatic microsomes. There was no significant difference in the in vitro stabilities of dimethylmitozolomide and methylmitozolamide with half-lives of 43.5 and 45.8 min, respectively, in RPMI at 37 degrees C. The in vitro microsomal incubation of dimethylmitozolomide produced significant amounts of methylmitozolomide, which suggests that methylmitozolomide contributed to the cytotoxicity of dimethylmitozolomide in the presence of microsomes. The pharmacokinetics of both dimethylmitozolomide and methylmitozolomide, given i.p. at 10 mg/kg, were investigated in CBA/Ca mice bearing the s.c. solid TLX5 lymphoma. Methylmitozolomide was absorbed rapidly with maximum plasma and tumor concentrations of 10.66 mg/liter and 8.01 mg/kg, respectively, achieved 0.17 h following dosing. Dimethylmitozolomide was also rapidly absorbed with maximum plasma and tumor concentrations of 9.34 mg/liter and 5.00 mg/kg, respectively, achieved within 0.18 h of dosing. Following administration of dimethylmitozolomide, methylmitozolomide was found in both plasma and tumor tissue. The plasma and tumor area under the curves of methylmitozolomide were 87.7% and 120.8%, respectively, of those seen when mice were dosed with authentic methylmitozolomide. By comparison of the area under the curves and clearance values, it was demonstrated that 89% of the administered dimethylmitozolomide was metabolized via methylmitozolomide.

Use of a patient information system to audit the introduction of modified early warning scoring.

Modified early warning scoring (MEWS) uses abnormalities in routine observations to identify patients at risk of critical illness. Nurses recorded scores at or above the medical response score of 3 on a hospital clinical information system during the first year of introducing MEWS to 10 wards in a university hospital. A total of 619 triggers were recorded in 365 patients. Fifty-nine required intensive care unit (ICU)/high dependency unit (HDU) care; 71 died. Survival was significantly worse for initial scores >4 (35/104 patients died) than for scores 3-4 (P<0.004). Multivariant analysis showed age (P<0.001) and trigger score (P<0.001) but not ward specialty (P=0.1) predicted death. Mean ages of survivors and non-survivors were 64 years (SD 18) and 74 years (SD 17), respectively. Addition of a score for age did not significantly increase the area under a receiver operator characteristic curve for the predictive value of MEWS scores. The study shows that increasing MEWS score is associated with worse outcome across a range of specialties and that nursing staff will use a patient information system to audit MEWS scores.

Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide.

The present study tested the hypothesis that the experimental antineoplastic imidazotetrazinone temozolomide degrades in the biophase to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and exerts its cytotoxicity via this species. MTIC is a metabolite of the antimelanoma agent dacarbazine and is thought to be responsible for the antineoplastic activity of the latter. Cytotoxicity in vitro was investigated in TLX5 murine lymphoma cells. MTIC and temozolomide were cytotoxic in the absence of mouse-liver microsomes, whereas dacarbazine required metabolic activation. The generation of MTIC from either dacarbazine, its primary metabolite 5-[3-(hydroxymethyl)-3-methyl-triazen-1-yl]-imidazole-4-carboxamid e (HMMTIC) or temozolomide was studied by reversed-phase high-performance liquid chromatography in incubation mixtures under the conditions of the cytotoxicity assay. MTIC was found in incubations of temozolomide with or without microsomes. Dacarbazine yielded MTIC (and HMMTIC) only when microsomes were included in the incubation mixture. Although the mode of action of temozolomide seems to be similar to that of dacarbazine, the results obtained in this study show that these agents differ markedly in their ability to generate the active species MTIC.

The effect of age on the pharmacokinetics of oxprenolol.

The pharmacokinetics of oxprenolol have been studied in young and healthy elderly volunteers. Drug concentrations in plasma and urine have been measured after a single 80-mg dose of oxprenolol and again after repeated administration (80 mg twice daily) for a period of 1 week. It has been shown that multiple dosing does not result in oxprenolol accumulation in either group and that age has no effect on the pharmacokinetics of this drug.

The effect of age on the pharmacokinetics of metoprolol and its metabolites.

1 Plasma concentrations of metoprolol and a pharmacologically active metabolite, H119/66, have been measured in young and elderly volunteers after a single dose of 100 mg metoprolol tartrate and after repeated administrated over a period of 1 week. Whilst concentrations of metoprolol are similar in each group, concentrations of H119/66 are approximately twice as high in the elderly. 2 Concentrations of unchanged metoprolol and of the major, but pharmacologically inactive, metabolite, H117/04, together with the two active metabolites of metoprolol have been determined in urine. Only the excretion of metoprolol was diminished in the elderly. 3 Areas under the plasma concentration curve for metoprolol after repeated administration are greater than would be predicted from single dose data, and possible explanations for this are discussed. Concentrations of the pharmacologically active metabolite, H119/66, remain unaltered during chronic dosing of metoprolol. 4 This study has shown that the effect of age on the pharmacokinetics of metoprolol and its metabolites is less pronounced than that observed for other drugs.

Lack of evidence for polymorphism in metoprolol metabolism.

The claim for polymorphism in the metabolism of metoprolol is based on a logical fallacy. A frequency distribution of metoprolol AUC data is presented and, although highly skewed, no evidence of more than a single population is apparent. Plasma and urine metoprolol and metabolite data are also presented to support this.

Effect of inflammatory disease on plasma concentrations of three beta-adrenoceptor blocking agents.

Plasma concentrations of three beta-adrenoceptor blocking agents, propranolol, oxprenolol, and metoprolol, have been measured over 24 h after a single oral dose in patients with active inflammatory disease, and in healthy subjects. After propranolol administration, peak plasma concentrations were approximately seven times higher in the patients; they remained significantly raised at all sampling times up to 10 h. With oxprenolol, peak plasma levels were about twice as high in the patients as in the healthy subjects and significantly raised on only two occasions. All plasma metoprolol values were within normal limits. These results did not run parallel with differences in metabolism between the three drugs, but did seem to relate to their degree of binding to plasma proteins (propranolol 93%, oxprenolol 80%, metoprolol 11%). Furthermore, it is known that propranolol binds to serum orosomucoid, an acute-phase reactant, which rises in inflammatory disease.

A single and multiple dose pharmacokinetic and pharmacodynamic comparison of conventional and slow-release metroprolol.

Pharmacokinetic and pharmacodynamic profiles for metoprolol have been measured in six healthy volunteers after single and multiple dosing with 100 mg conventional formulation twice daily and 200 mg slow-release formulation once daily. Both multidose regimes produced measurable predosing plasma concentrations of metoprolol. The plasma concentrations on the eighth day were greater than predicted by the single-dose data as indicated by the comparison of the total areas under the curve for the single dose and the dosage interval areas during multiple dosing. This increase may be associated with a change in the bioavailability and/or clearance of the drug and is currently being investigated. The peak concentrations for the two regimens were comparable but the times to peak with the slow-release regimen were significantly delayed. Both regimes produced significant beta-blocking effects over 24 h during multiple dosing, the reductions in exercise heart rate at 0 and 24 h on the eighth day corresponding to more than 20% of the maximum effect. Resting pulse rates and blood pressures were affected to a similar extent by the two regimens but neither significantly altered respiratory peak flow rates. The effects during multiple dosing were generally greater than those after a single dose and appeared to follow a more consistent trend. This observation, together with those for the plasma level data on the eighth day, illustrate the importance of performing multiple-dose studies in assessing beta-blocking drugs.

Effects of inflammatory disease on plasma oxprenolol concentrations.

When single oral doses of oxprenolol were given to three healthy subjects on three separate occasions under standardised conditions the plasma concentration-time curves for each subject were closely similar. In two of the subjects, however, a mild illness led to a dramatic, temporary increase in the peak plasma concentration and area under the plasma concentration-time curve (AUC). This effect of inflammatory disease was confirmed by comparing a group of patients with an erythrocyte sedimentation rate (ESR) of over 20 mm in the first hour with a group whose ESR was below this value. The mean peak plasma concentration and AUC were significantly higher in the group with a raised ESR. This may be related to altered concentrations of one of the acute-phase proteins. Thus it is concluded that plasma oxprenolol concentrations are raised in inflammatory disease, but further work is needed to determine the mechanism of this increase.

A pharmacokinetic and pharmacodynamic assessment of a combined slow-release metoprolol-chlorthalidone preparation.

Beta adrenoceptor blocking drugs and diuretics are frequently given together to control hypertension and increasingly the two agents are being combined in a single preparation. Possible interactions between the two agents are therefore of interest. In this study the addition of chlorthalidone has been shown not to influence the plasma levels or beta-blocking action of a sustained release form of metoprolol. In addition, when the combination product containing sustained release metoprolol and chlorthalidone is given over 21 days, the plasma levels of each drug are similar to those reported for each drug when given alone.

Variability of beta-blocker pharmacokinetics in young volunteers.

Plasma concentrations of metoprolol, propranolol oxprenolol, acebutolol and its metabolite diacetolol were measured after single oral doses in young health volunteers. In order to assessed the inter- and intra-subject variability the following pharmacokinetic parameters were compared: AUC0(24), Cmax, tmax and t 1/2. The smallest variation in inter-subject variability was seen with oxprenolol and acebutolol: intrasubject variability was more uniform. Female volunteers taking an oral contraceptive generally had higher AUC0(24) and Cmax values than those not. This finding reached statistical significance only for metoprolol AUC0(24).

Metoprolol pharmacokinetics and the oral contraceptive pill.

PIP: The authors determined plasma levels of metoprolol, a widely used beta-adrenoceptor blocker, following oral administration of 100 mg to 23 women. 1/2 of this group were taking a combined estrogen-ethinyl estradiol low dose oral contraceptive (OC). Blood samples were taken before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dosing. The volunteers were supine for 8 hours, then the cannula was removed, the patients were allowed up, and the last 2 samples were obtained by venepuncture. The concentration of metoprolol in plasma was determined by a modification of the Jack and Riess method. The average age of the control group was 20.7 years compared with 20.5 for the pill group. The difference in AUC between the 2 groups was significant at the P=0.05 level (metoprolol control-662; metoprolol OC-1051). No other parameters displayed statistical significance. Metoprolol plasma concentrations were higher in women taking the pill and the difference was significant. The AUC increase with no change in t 1/2 is consistent with an inhibitory effect of the pill on hepatic microsomal oxidase. Hepatic drug elimination is determined mainly by the activity of the drug metabolizing enzymes and hepatic blood flow. Drugs such as metoprolol with a high extraction ratio do not show changes in clearance and 1/2-life if hepatic enzymes are inhibited. Smoking is known to induce drug metabolizing enzymes and this must be considered. The clinical importance of the interaction between beta-adrenoceptor blockers and OCs is probably small since the overlap between the 2 groups is small. These results, however, suggest that beta-adrenoceptor blocker metabolism may be influenced by the effects of other drugs which inhibit microsomal enzyme activity. Presently, there is research underway to examine the effects of OCs on other beta-adrenoceptor blockers.^ieng

Beta-adrenoceptor blocker pharmacokinetics and the oral contraceptive pill.

Higher AUC and Cmax values were obtained for metoprolol, oxprenolol and propranolol in groups receiving the low-dose oestrogen-ethinyl oestradiol oral contraceptive, but statistical significance was reached only with metoprolol AUC. The oral contraceptive had the opposite effect on acebutolol AUC and Cmax but this was not significant. The oral contraceptive had no detectable effects on the tmax and t 1/2 values of any of the beta-adrenoceptor blockers.

Comparison of the pharmacodynamic and pharmacokinetic profiles of single and multiple doses of a commercial slow-release metoprolol formulation with a new Oros delivery system.

1 A new osmotic pressure mediated delivery system for metoprolol (Lopresor Oros) has been evaluated by measuring the haemodynamic effects and pharmacokinetics after single and multiple oral dosing in young healthy volunteers. 2 Similar studies have been carried out in the same group using equivalent single and multiple oral doses of the commercial slow-release preparation (Slow Lopresor). 3 The new osmotic delivery system produces a more uniform haemodynamic response: a plateau metoprolol concentration in plasma is reached about 6 h after dosing and is maintained for 10 h.

Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856).

Temozolomide (CCRG 81045: M&B 39831: NSC 362856) is an analogue of mitozolomide displaying similar broad spectrum activity in mouse tumours, but showing considerably less myelosuppression in the toxicology screen. Temozolomide was initially studied intravenously at doses between 50-200 mg m-2 and subsequently was given orally up to 1,200 mg m-2. A total of 51 patients were entered on the single dose schedule. Temozolomide exhibits linear pharmacokinetics with increasing dose. Myelotoxicity was dose limiting. Experimentally, temozolomide activity was schedule dependent and therefore oral administration was studied as a daily x 5 schedule between total doses of 750 and 1,200 mg m-2 in 42 patients. Myelosuppression was again dose limiting. The recommended dose for Phase II trials is 150 mg m-2 po for 5 days (total dose 750 mg m-2) for the first course, and if no major myelosuppression is detected on day 22 of the 4 week cycle, the subsequent courses can be given at 200 mg m-2 for 5 days (total dose 1 g m-2) on a 4 week cycle. Mild to moderate nausea and vomiting was dose related but readily controlled with antiemetics. Clinical activity was detected using the 5 day schedule in four (2CR, 2PR; 17%) out of 23 patients with melanoma and in one patient with mycosis fungoides (CR lasting 7 months). Two patients with recurrent high grade gliomas have also had partial responses. Temozolomide is easy to use clinically and generally well tolerated. In the extended Phase I trial temozolomide only occasionally exhibited the unpredictable myelosuppression seen with mitozolomide.