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1. Allopurinol usage in 50 patients of a city teaching hospital was surveyed. 2. The plasma concentrations of oxipurinol and uric acid and the urinary production of uric acid were examined. 3. The daily doses of allopurinol ranged from 50 to 1200 mg but 83% of patients were taking 300 mg daily. 4. A wide range of plasma oxipurinol concentrations was observed from 2.8 to 55.8 mg l-1 with a mean +/- s.d. of 15.2 +/- 11.7 mg l-1. 5. The population studied included a high proportion of patients with renal impairment and creatinine clearance was a significant determinant of oxipurinol concentrations (P less than 0.005). 6. There was no significant correlation between plasma urate and plasma oxipurinol concentrations and only a few plasma urates were above the upper limit of the reference range of the laboratory. 7. It was apparent that many patients were taking unnecessarily high daily doses of allopurinol and that renal status was not always considered when deciding dosage regimens of allopurinol. [ABSTRACT FROM AUTHOR]

Nine healthy male volunteers were studied to assess the possibility of an interaction between theophylline and nifedipine or verapamil using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without nifedipine 20 mg 12 hourly and verapamil 80 mg 8 hourly. Nifedipine treatment reduced mean total theophylline clearance by 9%, due to decreased clearances via 1- and 3- demethylation. Verapamil treatment reduced mean total theophylline clearance by 14%, due to decreased clearances via 1- and 3- demethylation and 8-hydroxylation. Verapamil and nifedipine at usual clinical doses are unlikely to cause clinically significant changes in theophylline disposition. [ABSTRACT FROM AUTHOR]

1. A radiometric high performance liquid chromatographic method is described for the assay of theophylline metabolism in vitro by the microsomal fraction of human liver. 2. Formation of the three metabolites of theophylline (3-methylxanthine, 1-methylxanthine and 1,3- dimethyluric acid) were linear with protein concentrations to 4 mg ml-1 and with incubation times up to 180 min. 3. The coefficients of variation for the formation of 3-methylxanthine, 1-methylxanthine and 1,3-dimethyluric acid were 1.2%, 1% and 1.6%, respectively. 4. Theophylline is metabolised by microsomal enzymes with a requirement for NADPH. 5. The mean (n = 7) Km values for 1-demethylation, 3- demethylation and 8-hydroxylation were 545, 630 and 788 microM, respectively, and the mean Vmax values were 2.65, 2.84 and 11.23 pmol min-1 mg-1, respectively. 6. There was a high correlation between the Km and Vmax values for the two demethylation pathways suggesting that the demethylations are performed by the same enzyme. 7. Overall the in vitro studies are consistent with the in vivo results which suggest the involvement of two cytochrome P-450 isozymes in the metabolism of theophylline. [ABSTRACT FROM AUTHOR]

Two groups of six healthy male volunteers were studied to assess the possibility of an interaction between dextropropoxyphene and theophylline or tolbutamide using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly or tolbutamide 500 mg i.v. with and without dextropropoxyphene hydrochloride 65 mg 8 hourly. Theophylline 8-hydroxylation was reduced by a mean of 17% but there were no changes in theophylline 1-demethylation, theophylline 3- demethylation or tolbutamide hydroxylation. [ABSTRACT FROM AUTHOR]

Paracetamol disposition was studied in groups of pregnant and non- pregnant women of comparable age. Paracetamol apparent oral clearance was 58% higher and elimination half-life was 28% lower in the pregnant women compared to the control group. The higher clearance in the pregnant women was due to increased activity of the glucuronidation (75% higher) and oxidative (88% higher) pathways of paracetamol metabolism. There was no difference between the two groups in paracetamol sulphation or renal clearance of unchanged drug. [ABSTRACT FROM AUTHOR]

Five subjects who participated in an earlier study (Lelo et al., 1986b) of the comparative pharmacokinetics of caffeine (CA) and its primary monodemethylated metabolites paraxanthine (PX), theobromine (TB) and theophylline (TP) were administered CA to steady-state. Using areas under the plasma concentration-time curves for each of the dimethylxanthines derived from CA in the steady-state study and individual plasma clearances of PX, TB and TP determined in the previous study, the fractional conversion of CA to PX, TB and TP and the individual partial clearances of CA have been defined. The mean (+/- s.d.) fractional conversion of CA to PX, TB and TP was 79.6 +/- 21.0%, 10.8 +/- 2.4% and 3.7 +/- 1.3%, respectively. When only demethylation pathways are considered PX, TB and TP accounted for 83.9 +/- 5.4%, 12.1 +/- 4.1% and 4.0 +/- 1.4%, respectively of the CA demethylations. The mean partial clearance of CA to PX was approximately 8-fold and 23-fold greater than those to TB and TP respectively. These data confirm earlier reports that PX is the major metabolite of CA in humans but suggest that PX formation is quantitatively more important than previously believed. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in six healthy male volunteers after oral administration of each compound on separate occasions. The total plasma clearances of CA and PX were similar in value (2.07 and 2.20 ml min-1 kg-1, respectively) as were those for TP and TB (0.93 and 1.20 ml min-1 kg-1, respectively). The unbound plasma clearances of CA and PX were also similar in magnitude (3.11 and 4.14 ml min-1 kg-1, respectively) as were those of TP and TB (1.61 and 1.39 ml min-1 kg-1, respectively). The half-lives of TP and TB (6.2 and 7.2 h, respectively) were significantly longer than those of CA and PX (4.1 and 3.1 h, respectively). The volume of distribution at steady state of TP (0.44 l kg-1) was lower than that of the other methylxanthines (0.63- 0.72 l kg-1). The unbound volume of distribution of TP (0.77 l kg-1) was however the same as that of TB (0.79 l kg-1) whereas the unbound volume of distribution of PX (1.18 l kg-1) was similar to that of CA (1.06 l kg-1). [ABSTRACT FROM AUTHOR]

Salicylic acid and acetylsalicylic acid (aspirin) disposition after an oral dose of aspirin, 900 mg (equivalent to 689.7 mg of salicylic acid) was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Salicylic acid clearance was 61% higher in males compared to the control female group, an effect due largely to enhanced activity of the glycine conjugation pathway (salicyluric acid formation) in males. Salicylic acid clearance was 41% higher in OCS-users compared to the control female group due to increases in both the glycine and glucuronic acid conjugation pathways in the pill users. There was no difference in any salicylic acid disposition parameter between males and OCS-users. Area under the plasma concentration-time curve (AUC) and elimination half-life of aspirin was significantly greater and aspirin plasma hydrolysis rate was significantly lower in both female groups compared to males. There was no difference between OCS-users and the control female group in any of these parameters. Aspirin AUC and elimination half-life were significantly correlated with aspirin plasma hydrolysis rate. These data confirm the importance of hormonal factors in the regulation of drug conjugation reactions in humans and suggest that sex-related differences in salicylic acid and aspirin disposition may be of clinical importance. [ABSTRACT FROM AUTHOR]

The effect of separate pretreatments with cotrimoxazole, sulphamethoxazole and trimethoprim on the disposition of tolbutamide was studied in seven healthy males. Tolbutamide 500 mg intravenously was administered on four separate occasions-as a control without pretreatment and on the seventh day of separate twice daily administration of cotrimoxazole (sulphamethoxazole 800 mg plus trimethoprim 160 mg) (ST phase), sulphamethoxazole 1 g (S phase) and trimethoprim 150 mg (T phase). Tolbutamide total and unbound plasma clearance (CL) were reduced following each of the individual pretreatments compared to the control phase (P less than 0.001). For unbound CL the reductions were 14% in the S and T phases and 25% in ST phase. Tolbutamide elimination half-life was prolonged following each pretreatment (P less than 0.001) by 20% in the S phase, 19% in the T phase and 30% in the ST phase. Tolbutamide total steady-state volume of distribution (VSS) was increased by 10% in the S and ST phases (P less than 0.01), the increase being accounted for by an increase in tolbutamide unbound fraction. There was no change in tolbutamide unbound VSS following any of the pretreatments. These results are consistent with inhibition of tolbutamide oxidation by cotrimoxazole, an additive effect of the two components sulphamethoxazole and trimethoprim. Sulphamethoxazole also reduces tolbutamide plasma protein binding. [ABSTRACT FROM AUTHOR]

The effects of separate 5 day pretreatments of propranolol 120 mg day-1 and 720 mg day-1 on theophylline clearance and metabolism at steady- state were determined in seven healthy males. Propranolol 120 mg day-1 decreased theophylline plasma clearance (CL) by 30%. Clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylated products by 42-43% and clearance to the 8-hydroxylation product by 27%. Propranolol 720 mg day-1 decreased theophylline CL by 52%. Again, clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylation products by 73-77% and clearance to the 8-hydroxylation product by 44%. These data are consistent with a dose-dependent and selective inhibitory effect of propranolol on the separate forms of cytochrome P-450 involved in theophylline demethylation and 8- hydroxylation. [ABSTRACT FROM AUTHOR]

The effect of pretreatment with ranitidine (150 mg twice daily for 5 days) on the disposition of lignocaine was examined in 10 healthy volunteers (five male, five female). Each subject received separate oral (250 mg) and intravenous (1.5 mg/kg) doses of lignocaine hydrochloride before and after ranitidine. Lignocaine systemic clearance was reduced by 9% (1.11 to 0.99 1 h-1 kg-1; P less than 0.01) following ranitidine pretreatment. The volume of distribution at steady- state was reduced by 15% (3.34 to 2.85 1 kg-1; P less than 0.005). Lignocaine oral clearance, elimination half-life and oral bioavailability were unchanged after ranitidine pretreatment. There was no sex difference in the effects of ranitidine pretreatment on lignocaine disposition. These results are consistent with small reductions in blood flow to the splanchnic and other vascular beds due to ranitidine. [ABSTRACT FROM AUTHOR]

The effects of separate 7 day pretreatments with sulphinpyrazone (800 mg daily) and cimetidine (1 g daily) on the disposition of (+/-)- verapamil have been examined in eight healthy volunteers (four male, four female). Each subject received single oral (80 mg) and intravenous (0.15 mg/kg) doses of verapamil on different occasions before and after each pretreatment. Following sulphinpyrazone pretreatment, verapamil apparent oral plasma clearance (CLpo) increased from 4.27 to 13.77 l h- 1 kg-1 (s.e. mean 0.51-ANOVA) (P less than 0.001); CL increased from 1.05 to 1.20 l h-1 kg-1 (s.e. mean 0.05) (P less than 0.05) and Fpo decreased from 27 to 10% administered dose (s.e. mean 2) (P less than 0.001). Vss and t1/2,z were unchanged. There was no sex difference for any dispositional parameter in the control phase, but the increase in CLpo following sulphinpyrazone pretreatment was more marked in males (4.04 to 17.33 l h-1 kg-1) than in females (4.49 to 10.21 l h-1 kg-1) (s.e. mean 0.72) (P less than 0.01). There was no significant change in any verapamil disposition parameter following cimetidine pretreatment. Verapamil unbound fraction in plasma was 0.157 (s.e. mean 0.001, n = 40). There was no alteration in verapamil plasma protein binding associated with increasing verapamil concentration (25-250 micrograms l- 1) or addition of sulphinpyrazone (50-500 mg l-1) or cimetidine (0.5-5 mg l-1). The results suggest that sulphinpyrazone induces the metabolic clearance of (+/-)-verapamil with a sex difference in the response.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The effects of separate 1 week pre-treatments with each of the beta- adrenoceptor antagonists, propranolol (80 mg every 12 h), metoprolol (100 mg every 12 h) and atenolol (50 mg once daily), on the disposition of a single i.v. dose of tolbutamide were studied in six healthy volunteers. In addition, the effects of a 1 week pre-treatment with metoprolol (100 mg every 12 h) and atenolol (50 mg once daily) on the disposition of orally and i.v. administered lignocaine were determined in seven healthy subjects. Tolbutamide clearance, half-life, volume of distribution and plasma protein binding were not altered by the beta- adrenoceptor blocker pre-treatments. Similarly, neither metoprolol nor atenolol had a significant effect on the systemic clearance, apparent oral clearance or other dispositional parameters of lignocaine. 'Therapeutic' plasma concentrations of the beta-adrenoceptor blockers were confirmed on each study day. It is concluded that the inhibition of oxidative drug metabolism previously reported for lipophilic beta- adrenoceptor blockers may be selective for different forms of cytochrome P450 and possible concentration-dependent. [ABSTRACT FROM AUTHOR]

The effect of rifampicin pre-treatment (600 mg daily for 6 days) on theophylline disposition at steady state was investigated in six healthy males. Following rifampicin treatment total plasma clearance of theophylline increased by 82%. Theophylline clearance through each metabolic pathway was increased, 1-demethylation by (116 +/- 34%) (mean +/- s.e. mean), 3-demethylation by (91 +/- 16%) and 8-oxidation by (81 +/- 17%). Renal clearance of unchanged drug was not altered. Previous studies have suggested that two forms of cytochrome P-450 are involved in theophylline metabolism, one mediating the N-demethylations and the other 8-oxidation. Thus, unlike the selective inductive effect of rifampicin on antipyrine metabolic pathways, rifampicin does not differentially affect those forms of cytochrome P-450 involved in theophylline metabolism. The extent to which theophylline metabolism is induced by rifampicin is likely to have important clinical consequences. [ABSTRACT FROM AUTHOR]

The disposition of clofibric acid, a drug metabolised largely by glucuronidation, was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Clofibric acid plasma clearance was not significantly different in males compared to the control female group but was 48% greater (P less than 0.01) in women receiving OCS compared to non-pill using females. This difference was due to an alteration in clofibric acid metabolic clearance as there were no differences between the groups in clofibric acid free fraction. Along with previous data the results suggest that induction of drug glucuronidation by OCS may be of clinical importance, although any sex- related differences are unlikely to be of clinical significance. [ABSTRACT FROM AUTHOR]

Ranitidine disposition has been studied in 12 patients with renal impairment following 50 mg given intravenously and 150 mg given by mouth on separate occasions. The clearance of ranitidine from plasma (y) was correlated with creatinine clearance (x): y = 10.47 + 0.289x,r2 = 0.751, but there was no significant correlation of creatinine clearance with distribution volume or bioavailability. The mean (s.e. mean) distribution volume was 1.62 (0.08) 1/kg and the mean bioavailability 0.81 (0.05). These data suggest that in order to obtain similar ranitidine plasma concentrations in anephric patients and patients with normal renal function, the maintenance dose in the anephric patients should be 25-30% of that for patients with normal renal function. [ABSTRACT FROM AUTHOR]

Paracetamol metabolism was investigated in eight healthy males, eight healthy females and eight healthy females receiving oral contraceptive steroids (OCS). Paracetamol clearance was 22% greater in males compared to the control female group. This difference was entirely due to increased activity of the glucuronidation pathway in males, there being no sex-related differences in the sulphation or oxidative metabolism of paracetamol. Paracetamol clearance in females using OCS was 49% greater than in the control females. Glucuronidation and oxidative metabolism were both induced in OCS users (by 78% and 36% respectively) but sulphation was not altered. Although sex-related differences in paracetamol metabolism are unlikely to be of clinical importance, induction of paracetamol metabolism by OCS may have clinical and toxicological consequences. [ABSTRACT FROM AUTHOR]

Paracetamol disposition following a single oral 1 g dose of the drug was compared in groups (n = 12) of healthy young adult male Caucasians and Chinese. There was no difference between the groups in terms of paracetamol oral clearance, elimination half-life, or partial metabolic (glucuronidation, sulphation, oxidation) and renal clearances. The results demonstrate that drug glucuronidation is not universally impaired in Chinese and, together with previously published data, that paracetamol glucuronidation is minimally affected by race. [ABSTRACT FROM AUTHOR]

The effects of sulphinpyrazone administration on the metabolic and renal clearances of theophylline in man were investigated. Sulphinpyrazone increased total plasma theophylline clearance by 22%. This was the sum of increases in metabolic clearances by 3- demethylation (32%), 1-demethylation (30%) and 8-oxidation (22%) and of a decrease in renal clearance (27%). It is proposed that sulphinpyrazone has differential effects on at least two forms of cytochrome P-450 inhibiting one enzyme or group of enzymes which metabolises tolbutamide, phenytoin and S(-)warfarin and inducing a form (or forms) which metabolises theophylline, antipyrine and R(+)warfarin. [ABSTRACT FROM AUTHOR]

The route of formation of 1-methyluric acid (1MU) from theophylline has been investigated by i.v. administration of 1-methylxanthine (1MX) before and after allopurinol treatment and of 1,3-dimethyluric acid (1,3DMU) to healthy male volunteers. 1,3DMU was recovered unchanged in urine and was not demethylated to 1MU. By contrast after administration of 1MX the major part of the dose was recovered as 1MU. After allopurinol this was reversed with most of the 1MX dose being excreted unchanged and only a minor amount as 1MU. The results show that 1MU derived from theophylline is formed by an initial 3-demethylation to 1MX and then a rapid xanthine oxidase mediated 8-oxidation. No 1MU is formed by 3-demethylation of 1,3DMU. [ABSTRACT FROM AUTHOR]

Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of nonsteroidal anti-inflammatory drugs in vitro. Here, we conducted molecular dynamics simulations (MDS) together with enzyme kinetic investigations and site-directed mutagenesis to elucidate the molecular basis of the activation of CYP2C9-catalyzed S-flurbiprofen 4'-hydroxylation and S-naproxen O-demethylation by dapsone. Supplementation of incubations of recombinant CYP2C9 with dapsone increased the catalytic efficiency of flurbiprofen and naproxen oxidation by 2.3- and 16.5-fold, respectively. MDS demonstrated that activation arises predominantly from aromatic interactions between the substrate, dapsone, and the phenyl rings of Phe114 and Phe476 within a common binding domain of the CYP2C9 active site, rather than involvement of a distinct effector site. Mutagenesis of Phe114 and Phe476 abrogated flurbiprofen and naproxen oxidation, and MDS and kinetic studies with the CYP2C9 mutants further identified a pivotal role of Phe476 in dapsone activation. MDS additionally showed that aromatic stacking interactions between two molecules of naproxen are necessary for binding in a catalytically favorable orientation. In contrast to flurbiprofen and naproxen, dapsone did not activate the 4'-hydroxylation of diclofenac, suggesting that the CYP2C9 active site favors cooperative binding of nonsteroidal anti-inflammatory drugs with a planar or near-planar geometry. More generally, the work confirms the utility of MDS for investigating ligand binding in CYP enzymes., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs. Interaction mechanisms, namely inhibition and induction of UDP-glucuronosyltransferase (UGT) enzymes and the potential interplay with drug transporters, are reviewed in detail, as is the clinical significance of known DDIs. Altered victim drug exposure arising from modulation of UGT enzyme activities is relatively common and, notably, the incidence and importance of UGT induction as a DDI mechanism is greater than generally believed. Numerous DDIs are clinically relevant, resulting in either loss of efficacy or an increased risk of adverse effects, necessitating dose individualisation. Several generalisations relating to the likelihood of DDIs can be drawn from the known substrate and inhibitor selectivities of UGT enzymes, highlighting the importance of comprehensive reaction phenotyping studies at an early stage of drug development. Further, rigorous assessment of the DDI liability of new chemical entities that undergo glucuronidation to a significant extent has been recommended recently by regulatory guidance. Although evidence-based approaches exist for the in vitro characterisation of UGT enzyme inhibition and induction, the availability of drugs considered appropriate for use as 'probe' substrates in clinical DDI studies is limited and this should be a research priority., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The introduction of COVID-19 therapies containing ritonavir has markedly expanded the scope of use for this medicine. As a strong cytochrome P450 3A4 inhibitor, the use of ritonavir is associated with a high drug interaction risk. There are currently no data to inform clinician regarding the likely magnitude and duration of interaction between ritonavir-containing COVID-19 therapies and small-molecule kinase inhibitors (KIs) in patients with cancer., Methods: Physiologically based pharmacokinetic modeling was used to conduct virtual clinical trials with a parallel group study design in the presence and absence of ritonavir (100 mg twice daily for 5 days). The magnitude and time course of changes in KI exposure when coadministered with ritonavir was evaluated as the primary outcome., Results: Dosing of ritonavir resulted in a > 2-fold increase in steady-state area under the plasma concentration-time curve and maximal concentration for six of the 10 KIs. When the KI was coadministered with ritonavir, dose reductions to between 10% and 75% of the original dose were required to achieve an area under the plasma concentration-time curve within 1.25-fold of the value in the absence of ritonavir., Conclusion: To our knowledge, this study provides the first data to assist clinicians' understanding of the drug interaction risk associated with administering ritonavir-containing COVID-19 therapies to patients with cancer who are currently being treated with KIs. These data may support clinicians to make more informed dosing decisions for patients with cancer undergoing treatment with KIs who require treatment with ritonavir-containing COVID-19 antiviral therapies.

The inhibitory effects of fifteen NSAIDs from six structurally distinct classes on human liver microsomal morphine glucuronidation were investigated. K i values of selected NSAIDs were generated and employed to assess DDI liability in vivo. Potent inhibition was observed for mefenamic acid and tolfenamic acid; respective IC 50 values for morphine 3- and 6-glucuronidation were 9.2 and 13.5 μM, and 5.3 and 8.3 μM. Diclofenac and celecoxib showed moderate inhibition with IC 50 values of 78 and 52 μM, and 83 and 214 μM, respectively. Estimated IC 50 values for the other NSAIDs screened were >100 μM. Mefenamic acid, diclofenac, and S-naproxen competitively inhibited morphine 3- and 6-glucuronidation, with the K i values of 11 and 12 μM, 110 and 76 μM, and 319 and 650 μM, respectively. Using the static mechanistic IVIVE approach, an approximate 40% increase in the AUC of morphine was predicted when co-administered with mefenamic acid, whereas the increase was <10% with diclofenac and S-naproxen. PBPK modeling predicted <15% increases in the morphine AUC from diclofenac and S-naproxen inhibition in virtual healthy and cirrhotic subjects. The data suggest that potential clinically significant DDIs arising from NSAID inhibition of morphine glucuronidation is unlikely, with the possible exception of some fenamates., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2021 The Japanese Society for the Study of Xenobiotics. All rights reserved.)

Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer 'atypical' antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT 1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT 1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT 1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp103 3.32 , TAAR1; Asp116 3.32 , 5HT 1A ). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT 1A . MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT 1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Antihypertensives and cancer have a complex relationship. Among the antihypertensives, renin--angiotensin system inhibitors have strong immune modulatory activities that may affect immune check point inhibitors-related outcomes in cancer patients. We evaluated the association between concomitant use of renin--angiotensin system inhibitors and other antihypertensive agents with survival/toxicity outcomes from atezolizumab., Methods: A post hoc analysis of individual patient data from seven clinical trials of lung, renal or urothelial cancers was performed. Users and nonusers of antihypertensive classes were compared for overall survival, progression-free survival and immune adverse events. Cox proportional hazards were calculated between the groups and reported as hazards ratio and 95% confidence interval (95% CI)., Results: Of the 3695 patients, 2539 were treated with atezolizumab and the rest with chemotherapy. Twenty-four percent of patients were on a renin--angiotensin system inhibitor at trial commencement. No statistically significant difference in overall survival (hazard ratio 0.92, 95% CI 0.79-1.07, P = 0.29), progression-free survival (hazard ratio 0.95, 95% CI 0.84-1.08, P = 0.42) or immune adverse events (odds ratio 0.94, 95% CI 0.76-1.15, P = 0.55) between renin--angiotensin system inhibitor users and nonusers were identified in the atezolizumab-treated cohort. Other classes of antihypertensives were also not associated with survival., Conclusion: Concomitant use of antihypertensives including RASi was not associated with survival and immune-related safety outcomes during atezolizumab therapy for solid cancers. Future studies should evaluate the association between antihypertensives and other ICI as well as ICI combination interventions in clinical trials and real-world settings., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Concomitant use of proton pump inhibitors (PPIs) may negatively affect the efficacy of anticancer drugs such as fluoropyrimidines in patients with colorectal cancer (CRC). The primary objective of this study was to assess whether there is an association between concomitant PPI use and survival outcomes in patients with CRC treated with a fluoropyrimidine-based chemotherapy., Patients and Methods: A secondary analysis of 6 randomized controlled clinical trials in patients with advanced CRC was conducted using individual patient data through data-sharing platforms. The outcome measures were progression-free survival and overall survival in PPI users and nonusers. Subgroup analysis included the type of chemotherapy, capecitabine versus 5-FU, line of therapy, and addition of a vascular endothelial growth factor receptor inhibitor. Overall pooled hazard ratios (HRs) with 95% confidence intervals were calculated using a random effects model., Results: A total of 5,594 patients with advanced CRC across 6 trials and 11 trial arms were included; 902 patients were receiving a PPI at trial entry and initiation of chemotherapy. PPI use was significantly associated with worse overall survival (pooled HR, 1.20; 95% CI, 1.03-1.40; P=.02; I2 for heterogeneity = 69%) and progression-free survival (overall pooled HR, 1.20; 95% CI, 1.05-1.37; P=.009; I2 = 65%) after adjusting for clinical covariates. Furthermore, the association between concomitant PPI use and survival outcomes was similar across most treatment subgroups., Conclusions: We speculate that alterations in the gut microbiome, altered immune milieu within the tumor, and interactions through transporters are potential mechanisms behind this association between PPI use and chemotherapy in patients with CRC, which warrant further study. Concomitant use of PPIs is associated with worse survival outcomes in patients with CRC treated with fluoropyrimidine-based chemotherapy. Clinicians should cautiously consider the concomitant use of PPIs in such patients.

Enzymes of the UDP-glucuronosyltransferase (UGT) superfamily contribute to the elimination of drugs from almost all therapeutic classes. Awareness of the importance of glucuronidation as a drug clearance mechanism along with increased knowledge of the enzymology of drug and chemical metabolism has stimulated interest in the development and application of approaches for the characterisation of human drug glucuronidation in vitro, in particular reaction phenotyping (the fractional contribution of the individual UGT enzymes responsible for the glucuronidation of a given drug), assessment of metabolic stability, and UGT enzyme inhibition by drugs and other xenobiotics. In turn, this has permitted the implementation of in vitro - in vivo extrapolation approaches for the prediction of drug metabolic clearance, intestinal availability, and drug-drug interaction liability, all of which are of considerable importance in pre-clinical drug development. Indeed, regulatory agencies (FDA and EMA) require UGT reaction phenotyping for new chemical entities if glucuronidation accounts for ≥25% of total metabolism. In vitro studies are most commonly performed with recombinant UGT enzymes and human liver microsomes (HLM) as the enzyme sources. Despite the widespread use of in vitro approaches for the characterisation of drug and chemical glucuronidation by HLM and recombinant enzymes, evidence-based guidelines relating to experimental approaches are lacking. Here we present evidence-based strategies for the characterisation of drug and chemical glucuronidation in vitro, and for UGT reaction phenotyping. We anticipate that the strategies will inform practice, encourage development of standardised experimental procedures where feasible, and guide ongoing research in the field., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Guidance regarding the effect of codeine and its metabolites on foetal development is limited by small studies and inconsistent findings. The primary objective was to use physiologically based pharmacokinetic modelling to investigate the impact of gestational stage and maternal CYP2D6 phenotype on foetal morphine exposure following codeine administration. Full body physiologically based pharmacokinetic models were developed and verified for codeine and morphine using Simcyp (version 19.1). The impact of gestational age and maternal CYP2D6 phenotype on foetal and maternal morphine and codeine exposure following oral codeine administration was modelled in a cohort of 250 pregnant females and foetuses at gestational weeks 0 (mothers only), 6, 12, 24 and 36. Consistent with the known effect on codeine metabolism, a clinically meaningful (> 1.65-fold) increase in foetal morphine AUC was observed in the CYP2D6 UM phenotype cohort compared to the CYP2D6 EM and PM phenotype cohorts. The mean (95% CI) foetal morphine AUC in the CYP2D6 UM cohort of 0.988 (0.902 to 1.073) ng/mL.h was 1.8-fold higher than the CYP2D6 EM cohort of 0.546 (0.492 to 0.600) ng/mL.h (p < 0.001). Despite a 2.8-fold increase in maternal CYP2D6 protein abundance between gestational weeks 6 and 36, the mean foetal morphine AUC in the CYP2D6 EM and UM phenotype cohorts reduced by 1.55- and 1.75-fold, respectively, over this period. Maternal CYP2D6 phenotype is a significant determinant of foetal morphine AUC. Simulations suggest that the greatest risk with respect to foetal morphine exposure is during the first trimester of pregnancy, particularly in CYP2D6 UM phenotype mothers.

Glucuronidation, catalyzed by uridine diphosphate glucuronosyltransferases (UGTs), is an important process for the metabolism and clearance of many lipophilic chemicals, including drugs, environmental chemicals, and endogenous compounds. Glucuronidation is a bisubstrate reaction that requires the aglycone and the cofactor, UDP-GlcUA. Accumulating evidence suggests that the bisubstrate reaction follows a compulsory-order ternary mechanism. To simplify the kinetic modeling of glucuronidation reactions in vitro, UDP-GlcUA is usually added to incubations in large excess. Many factors have been shown to influence UGT activity and kinetics in vitro, and these must be accounted for during experimental design and data interpretation. While the assessment of drug-drug interactions resulting from UGT inhibition has been challenging in the past, the increasing availability of UGT enzyme-selective substrate and inhibitor "probes" provides the prospect for more reliable reaction phenotyping and assessment of drug-drug interaction potential. Although extrapolation of the in vitro intrinsic clearance of a glucuronidated drug often underpredicts in vivo clearance, careful selection of in vitro experimental conditions and inclusion of extrahepatic glucuronidation may improve the predictivity of in vitro-in vivo extrapolation. Physiologically based pharmacokinetic (PBPK) modeling has also shown to be of value for predicting PK of drugs eliminated by glucuronidation., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Enzymes of the human UDP-glycosyltransferase (UGT) superfamily typically catalyze the covalent addition of the sugar moiety from a UDP-sugar cofactor to relatively low-molecular weight lipophilic compounds. Although UDP-glucuronic acid (UDP-GlcUA) is most commonly employed as the cofactor by UGT1 and UGT2 family enzymes, UGT2B7 and several other enzymes can use both UDP-GlcUA and UDP-glucose (UDP-Glc), leading to the formation of glucuronide and glucoside conjugates. An investigation of UGT2B7-catalyzed morphine glycosidation indicated that glucuronidation is the principal route of metabolism because the binding affinity of UDP-GlcUA is higher than that of UDP-Glc. Currently, it is unclear which residues in the UGT2B7 cofactor binding domain are responsible for the preferential binding of UDP-GlcUA. Here, molecular dynamics (MD) simulations were performed together with site-directed mutagenesis and enzyme kinetic studies to identify residues within the UGT2B7 binding site responsible for the selective cofactor binding. MD simulations demonstrated that Arg259, which is located within the N-terminal domain, specifically interacts with UDP-GlcUA, whereby the side chain of Arg259 H-bonds and forms a salt bridge with the carboxylate group of glucuronic acid. Consistent with the MD simulations, substitution of Arg259 with Leu resulted in the loss of morphine, 4-methylumbelliferone, and zidovudine glucuronidation activity, but morphine glucosidation was preserved. SIGNIFICANCE STATEMENT: Despite the importance of uridine diphosphate glycosyltransferase (UGT) enzymes in drug and chemical metabolism, cofactor binding interactions are incompletely understood, as is the molecular basis for preferential glucuronidation by UGT1 and UGT2 family enzymes. The study demonstrated that long timescale molecular dynamics (MD) simulations with a UGT2B7 homology model can be used to identify critical binding interactions of a UGT protein with UDP-sugar cofactors. Further, the data provide a basis for the application of MD simulations to the elucidation of UGT-aglycone interactions., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Immune-related adverse events (irAEs) are known to occur in patients with cancer who are treated with immune checkpoint inhibitors. However, limited literature exists on the incidence, time of onset, and risk factors for irAEs, particularly those affecting multiple organs, associated with anti-PD-L1 inhibitors., Methods: A post hoc pooled analysis was conducted using individual patient data from atezolizumab monotherapy arms of 4 non-small cell lung cancer clinical trials. Incidence, clinical patterns, outcomes, and risk factors were investigated of selected organ-specific and multiorgan irAEs during treatment using the anti-PD-L1 inhibitor atezolizumab., Results: From a total of 1,548 patients, 730 irAE episodes were reported in 424 patients (27%). Skin irAEs were the most common (42%), followed by laboratory abnormalities (27%) and endocrine (11.6%), neurologic (7.6%), and pulmonary (6.2%) irAEs. A total of 84 patients (5.4%) had multiorgan irAEs, 70 had 2, 13 had 3, and 1 had 4 different organs affected. "Skin plus" or "laboratory plus" were the most common irAE multiorgan clusters. Patients with multiorgan irAEs were more likely to be white and have a good performance status, a lower baseline neutrophil-lymphocyte ratio, and a good or intermediate lung immune prognostic index score. Multiorgan irAEs were also associated with improved overall survival (hazard ratio, 0.47; 95% CI, 0.28-0.78; P<.0001) but not with progression-free survival (hazard ratio, 0.92; 95% CI, 0.62-1.35; P=.74) compared with the cohort with no irAEs., Conclusions: Multiorgan irAEs occurred in 5.4% of patients treated with atezolizumab in non-small cell lung cancer trials. Future trials should consider routine reporting of data on multiorgan toxicities in addition to organ-specific toxicities.

Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( K i * = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of -14.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even when most abiraterone has been eliminated systemically. Subsequent pharmacokinetic-pharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, in which equipotent reduction of downstream plasma DHEA-sulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for re-evaluating the current dosing paradigm of abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT: With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes., (U.S. Government work not protected by U.S. copyright.)

Clozapine is the gold-standard agent for treatment resistant schizophrenia but its mechanism of action remains unclear. There is emerging evidence of the potential role of the GABA B receptor in the pathogenesis of schizophrenia. It has been hypothesised that clozapine can mediate its actions via the GABA B receptor. Baclofen is currently recognised as the prototype GABA B receptor agonist. There are some potential clinical similarities between clozapine and baclofen. Indeed, baclofen has been previously proposed for use as an antipsychotic agent. Our analysis of the X-ray crystal structure of GABA B receptor along with molecular docking calculations, suggests that clozapine could directly bind to the GABA B receptor similar to that of baclofen. This finding could lead to a better understanding of the pharmacological uniqueness of clozapine, potential development of a biomarker for treatment resistant schizophrenia and the development of more targeted treatments leading to personalisation of treatment.

Importance: High body mass index (BMI) is independently associated with overall survival benefit from immune checkpoint inhibitor therapy in patients with melanoma, yet whether BMI is associated with outcomes in patients with advanced non-small cell lung cancer treated with atezolizumab remains unknown., Objective: To examine whether BMI is associated with survival outcomes and adverse events in patients with non-small cell lung cancer (NSCLC) treated with atezolizumab., Design, Setting, and Participants: A pooled analysis of individual patient-level data from 4 international, multicenter clinical trials was performed. Two were single-arm phase 2 trials (BIRCH [data cutoff of May 28, 2015] and FIR [data cutoff of January 7, 2015]), and 2 were 2-arm randomized clinical trials (POPLAR [phase 2; data cutoff of May 8, 2015] and OAK [phase 3; data cutoff of July 7, 2016]). Patients with advanced NSCLC previously untreated or treated with at least 1 line of systemic therapy, with measurable disease and good organ function and without contraindications for chemotherapy or immune checkpoint inhibitor therapy, were included in these trials. Data analyses were performed from February 28, 2019, to September 30, 2019., Interventions: The control group was treated with docetaxel once every 3 weeks until disease progression or unacceptable toxic effects occurred in POPLAR and OAK. The experimental group was treated with atezolizumab once every 3 weeks until disease progression or unacceptable toxic effects occurred in all available trials., Main Outcomes and Measures: Association between BMI and overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. Intention-to-treat analysis was conducted., Results: Adequate data were available for 2110 patients from a total pool of 2261 across 4 trials. Of those 2110, 1434 patients (median age, 64 years [range, 57-70 years]; 890 men [62%]) received atezolizumab and 676 patients (median age, 63 years[range, 57-69 years]; 419 men [62%]) received docetaxel. There was a linear association between increasing BMI and OS in patients treated with atezolizumab. Obesity (BMI ≥30 [calculated as weight in kilograms divided by height in meters squared]) was associated with significantly improved OS in patients treated with atezolizumab, but not in those who received docetaxel after adjusting for confounding variables. The association between BMI and OS/PFS was the strongest in the high PD-L1 expression subgroup. Overall survival for patients with the highest category of PD-L1 expression (≥50% of tumor cells or ≥10% of tumor-infiltrating immune cells; n = 436) had hazard ratios of 0.36 (95% CI, 0.21-0.62) for the group with obesity and 0.69 (95% CI, 0.48-0.98) for the group with overweight. Patients with the highest category of PD-L1 expression had PFS hazard ratios of 0.68 (95% CI, 0.49-0.94) for the group with obesity and 0.72 (95% CI, 0.56-0.92) for the group with overweight. Treatment-related adverse events were not associated with BMI., Conclusions and Relevance: High BMI appears to be independently associated with improved survival with atezolizumab in patients with NSCLC, raising the possibility that baseline BMI should be considered as a stratification factor in future immune checkpoint inhibitor therapy trials.

Purpose To validate a plasma vemurafenib steady-state trough concentration (C ss , min ) threshold that predicts survival outcomes of patients with BrafV 600 mutated melanoma., Methods: A pooled analysis of individual patient data from two advanced melanoma trials involving vemurafenib ± cobimetinib therapy was performed. Day 23 was chosen as the landmark time when steady-state concentration reached. Optimal C ss , min threshold was determined via assessment of discriminative performance and model fitting. Association between vemurafenib C ss , min and survival was modelled using Cox proportional hazards regression., Results: Vemurafenib plasma concentration data were available for 402 patients who were on stable dose for the first 3 weeks. When compared to a previously described plasma vemurafenib C ss , min threshold of 42 mg/L, we identified that a cutoff concentration of 50 mg/L by day 23 was strongly associated with progression-free survival and overall survival. The association remained statistically significant after adjusting for important clinical confounding variables. Sub-group analysis showed that while the addition of cobimetinib resulted in a lower day 23 plasma vemurafenib C ss , min , the threshold was still associated with overall survival and not in the monotherapy cohort., Conclusion: A plasma vemurafenib C ss , min threshold of 50 mg/L is strongly associated with survival outcomes in patients with advanced melanoma. This new threshold needs to be validated prospectively in future studies.