Aims To review (retrospectively) the relationships between lamotrigine (LTG) dosage and plasma concentrations based on data generated in a routine therapeutic drug monitoring laboratory from a heterogeneous sample of patients with epilepsy. To distinguish patients taking concomitant anti-epileptic therapy which induced or inhibited drug metabolising enzymes, or a combination of both, together with LTG. To survey medical staff who use a routine LTG assay service with a view to establishing the utility of higher plasma LTG concentrations than those used in early clinical trials. Methods All patient assays for LTG received over a 12 month period (339 requests from 149 patients) were reviewed and relationships between dosage and concentration calculated and grouped according to concomitant antiepileptic drug therapy. The doctors requesting the tests were surveyed by questionnaire (n=40 of 67 responded). They were asked for details about the patient's seizure control, rationale used for LTG dosage adjustment and their acceptance of the proposed 'therapeutic range' adopted by the laboratory of 3-14 mg l −1 .Results Linear relationships were demonstrated between LTG dosage and concentration for the 3 treatment groups (LTG plus valproic acid (VPA), LTG plus enzyme inducing antiepileptic drugs, and LTG plus VPA and inducers), however, there were significant differences between groups ( P<0.001) with a 4.4 fold difference in dosage5concentration ratios between the LTG plus VPA group and the LTG plus inducers group. The questionnaire showed that the therapeutic range was well accepted by 88% of responders, none of whom considered this higher range to be wrong. Conclusions Metabolic inhibition by VPA was shown to have a marked effect on LTG kinetics, suggesting either a significant LTG dosage reduction is required if plasma LTG concentrations are elevated, or alternatively, higher plasma LTG concentrations could be attained from lower dosages. The higher therapeutic range adopted by the laboratory (3-14 mg l −1 ) was widely accepted and increasingly applied in clinical practice in the management of patients with epilepsy.

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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 À Á . 2) To determine whether the ratio measured in the first fortnight of treatment C iOHPx =C i Px À Á 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 /Fj50 ml min x1 or C OHPx;ss /C Px;ss O0.3. A group of patients with CL Px /Fi950 ml min x1 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 x1 ), the variability in dose appeared directly proportional to CL Px /F (r 2 =0.741, P<0.0001). Study 2 (n=23).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 x1 , respectively, requiring doses of 10-25, 100-250 and 300-500 mg day x1 , respectively. Conclusions The cis-OH-perhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.

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Acyl glucuronides are a unique class of electrophilic metabolites, capable of non-enzymatic reactions including acylation and/or glycation of endogenous macromolecules, hydrolysis to reform the parent aglycone, and intra-molecular rearrangement. Three human UDP-glucuronosyltransferases (UGTs) catalyzing the hepatic glucuronidation of carboxylic acid drugs have been identified, UGT1A3, UGT1A9 and a UGT2B7 variant. Within the liver, acyl glucuronides also undergo enzymatic hydrolysis by beta-glucuronidase and esterases which, like the UGTs, are located in the endoplasmic reticulum. In addition, the liver also transports acyl glucuronides between the sinusoidal circulation and bile. Due to their polarity, membrane transport of acyl glucuronides is carrier-mediated, resulting in the establishment of significant concentration gradients between sinusoidal circulation, hepatocyte and bile, in the order of 1:50:5,000 in these compartments, respectively. As a result of exposure to high acyl glucuronide concentrations, the liver is a major target of protein adduct formation. Dipeptidylpeptidase IV, UGTs and tubulin have been identified as intra-hepatic targets of adduct formation by acyl glucuronides. Adduct formation results in altered protein activity and potentially contributes to hepatotoxicity. Hepatic protein adducts are also immunogenic and may cause immune mediated cytotoxicity. Both intra- and extra-hepatic exposure to acyl glucuronides depends not only on the efficiency of glucuronidation and hydrolysis by the liver, but also on the efficiency of the hepatic membrane transport systems. Thus, changes in membrane transporter activities, as may occur due to saturation or drug-drug interactions, can significantly affect acyl glucuronide disposition, adduct formation and the disposition of parent aglycone, thereby affecting clinical efficacy and toxicity of acyl glucuronide forming drugs.

1 The disposition of total and free prednisolone has been studied in four male and four female volunteers, each of whom received an intravenous dose of 0.075 mg/kg (low) and 1.5 mg/kg (high) of prednisolone at both 06.00 h and 18.00 h. 2 For the low dose, free prednisolone clearance was 14% lower (P = 0.012) and time-averaged prednisolone free fraction was 22% higher (P < 0.001) in the morning, there being no circadian difference in total prednisolone clearance. There was no circadian differences in prednisolone disposition at the high dose. These findings are consistent with a mechanism in which cortisol causes a simultaneous competitive inhibition of prednisolone clearance and plasma protein binding at low, but not at high prednisolone doses. 3 Prednisolone clearance was higher in female than in male subjects, the mean increase being 18% (P = 0.022) for total prednisolone and 21% (P = 0.036) for free prednisolone. 4 Mean total prednisolone clearance and steady-state distribution volume were two-fold higher at the high vs the low dose (P < 0.001), but free prednisolone clearance showed a dose dependent decrease of 11% (P = 0.019). There was no change in free prednisolone steady-state distribution volume.

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