Pharmacokinetics drug storage

Pharmacokinetics deals with the alterations of the drug by the body which includes absorption, distribution, binding/ storage, biotransformation and excretion of drugs. 

Pharmacokinetic characteristics of methyldopa are listed in Table 11-2. Methyldopa enters the brain via an aromatic amino acid transporter. The usual oral dose of methyldopa produces its maximal antihypertensive effect in 4-6 hours, and the effect can persist for up to 24 hours. Because the effect depends on accumulation and storage of a metabolite (a-methylnorepinephrine) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation. 

The plasma samples are stored for later analysis. The samples are analyzed using validated analytical methods. The most commonly used methods are chromatographic, i.e., HPLC or gas chromatography. These methods, including the storage conditions, must be validated so that accurate and precise results are assured. Pharmacokinetic parameters from the plasma drug release profiles are determined for individual volunteers. The average values of these parameters reflect the BA of the product. 

In spite of its rapid absorption and short half-life, the peak effect of methyldopa is delayed for 6 to 8 hours even after intravenons administration, and the duration of action of a single dose is nsnally about 24 hours this permits once-or twice-daily dosing. The discrepancy between the effects of methyldopa and the measured concentrations of the drug in plasma is most likely related to the time required for transport into the CNS, conversion to the active metabolite storage of a-methyl norepinephrine, and its subsequent release in the vicinity of relevant 0.2 receptors in the CNS. This is a good example of the potential for a complex relationship between a drug s pharmacokinetics and its pharmacodynamics. Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa, bnt it is not known if this is due to alteration in excretion of the drng or to an increase in transport into the CNS. 

A reverse-phase HPLC method with ESI-MS detection to characterize the pharmacokinetic behavior of procarbazine, a cytotoxic chemotherapeutic agent used in the treatment of lymphomas and hrain tumors. The data are used in a phase I trial concentrations are measured in human plasma. The calibration curve is linear in the 0.5-50 ng/ml concentration range. Average recovery rate 102.9%. Lower limit of quantitation 0.5 ng/ml accmacy 105.2% interday precision 3.6% RSD sample volume 150 p,l. Interday precisions at widely different concentrations 97-98%. The stability of the drug under storage and sample preparation conditions have also been thoroughly tested. Sensitivity is sufficient for monitoring plasma levels after oral administration. 

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