Foreskin restorers: insights into motivations, successes, challenges, and experiences with medical and mental health professionals - An abridged summary of key findings.

Demographically diverse surveys in the United States suggest that 5-10% of non-voluntarily circumcised American males wish that they had not been circumcised. Similar data are unavailable in other countries. An unknown proportion of circumcised males experience acute circumcision-related distress; some attempt to regain a sense of bodily integrity through non-surgical foreskin restoration. Their concerns are often ignored by health professionals. We conducted an in-depth investigation into foreskin restorers' lived experiences. An online survey containing 49 qualitative and 10 demographic questions was developed to identify restorers' motivations, successes, challenges, and experiences with health professionals. Targeted sampling was employed to reach this distinctive population. Invitations were disseminated to customers of commercial restoration devices, online restoration forums, device manufacturer websites, and via genital autonomy organizations. Over 2100 surveys were submitted by respondents from 60 countries. We report results from 1790 fully completed surveys. Adverse physical, sexual, emotional/psychological and self-esteem impacts attributed to circumcision had motivated participants to seek foreskin restoration. Most sought no professional help due to hopelessness, fear, or mistrust. Those who sought help encountered trivialization, dismissal, or ridicule. Most participants recommended restoration. Many professionals are unprepared to assist this population. Circumcision sufferers/foreskin restorers have largely been ill-served by medical and mental health professionals.

First-in-human clinical trial to assess the safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection.

AIMS: This first-in-human clinical trial of P218, a novel dihydrofolate reductase inhibitor antimalarial candidate, assessed safety, tolerability, pharmacokinetics and food effects in healthy subjects. METHODS: The study consisted of two parts. Part A was a double-blind, randomized, placebo-controlled, parallel group, ascending dose study comprising seven fasted cohorts. Eight subjects/cohort were randomized (3:1) to receive either a single oral dose of P218 (10, 30, 100, 250, 500, 750 and 1000 mg) or placebo. Part B was an open-label, cross-over, fed/fasted cohort (eight subjects) that received a 250 mg single dose of P218 in two treatment periods. RESULTS: P218 was generally well tolerated across all doses; 21 treatment-emergent adverse events occurred in 15/64 subjects. Nine adverse events in five subjects, all of mild intensity, were judged drug related. No clinically relevant abnormalities in ECG, vital signs or laboratory tests changes were observed. P218 was rapidly absorbed, with Cmax achieved between 0.5 and 2 hours post dose. Plasma concentrations declined bi-exponentially with half-life values ranging from 3.1 to 6.7 hours (10 and 30 mg), increasing up to 8.9 to 19.6 hours (doses up to 1000 mg). Exposure values increased dose-proportionally between 100 and 1000 mg for P218 (parent) and three primary metabolites (P218 ß-acyl glucuronide, P218-OH and P218-OH ß-acyl glucuronide). Co-administration of P218 with food reduced Cmax by 35% and delayed absorption by 1 hour, with no significant impact on AUC. CONCLUSION: P218 displayed favourable safety, tolerability and pharmacokinetics. In view of its short half-life, a long-acting formulation will be needed for malaria chemoprotection.

Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors.

Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.

Correction to: Antecedents of Emotional Distress and Sexual Dissatisfaction in Circumcised Men: Previous Findings and Future Directions-Comment on Bossio and Pukall (2017).

The term "body eudysmorphia" in the 6th paragraph of this Letter to the Editor incorrectly read "body dysmorphia" in the letter as originally published. The original article has been corrected.

Safety pharmacology in 2010 and beyond: survey of significant events of the past 10 years and a roadmap to the immediate-, intermediate- and long-term future in recognition of the tenth anniversary of the Safety Pharmacology Society.

In recognition of the tenth anniversary of the Safety Pharmacology Society (SPS), this review summarizes the significant events of the past 10years that have led to the birth, growth and evolution the SPS and presents a roadmap to the immediate-, intermediate- and long-term future of the SPS. The review discusses (i) the rationale for an optimal non-clinical Safety Pharmacology testing, (ii) the evolution of Safety Pharmacology over the last decade, (iii) its impact on drug discovery and development, (iv) the merits of adopting an integrated risk assessment approach, (v) the translation of non-clinical findings to humans and finally (vi) the future challenges and opportunities facing this discipline. Such challenges include the emergence of new molecular targets and new approaches to treat diseases, the rapid development of science and technologies, the growing regulatory concerns and associated number of guidance documents, and the need to train and educate the next generation of safety pharmacologist.

Value of non-clinical cardiac repolarization assays in supporting the discovery and development of safer medicines.

Non-clinical QT-related assays aligned to the pharmaceutical drug discovery and development phases are used in several ways. During the early discovery phases, assays are used for hazard identification and wherever possible for hazard elimination. The data generated enable us to: (i) establish structure-activity relationships and thereby; (ii) influence the medicinal chemistry design and provide tools for effective decision making; and provide structure-activity data for in silico predictive databases; (iii) solve problems earlier; (iv) provide reassurance for compound or project to progress; and (v) refine strategies as scientific and technical knowledge grows. For compounds progressing into pre-clinical development, the 'core battery' QT-related data enable an integrated risk assessment to: (i) fulfil regulatory requirements; (ii) assess the safety and risk-benefit for compound progression to man; (iii) contribute to defining the starting dose during the phase I clinical trials; (iv) influence the design of the phase I clinical trials; (v) identify clinically relevant safety biomarkers; and (vi) contribute to the patient risk management plan. Once a compound progresses into clinical development, QT-related data can be applied in the context of risk management and risk mitigation. The data from 'follow-up' studies can be used to: (i) support regulatory approval; (ii) investigate discrepancies that may have emerged within and/or between non-clinical and clinical data; (iii) understand the mechanism of an undesirable pharmacodynamic effect; (iv) provide reassurance for progression into multiple dosing in humans and/or large-scale clinical trials; and (v) assess drug-drug interactions. Based on emerging data, the integrated risk assessment is then reviewed in this article, and the benefit-risk for compound progression was re-assessed. Project examples are provided to illustrate the impact of non-clinical data to support compound progression throughout the drug discovery and development phases, and regulatory approval.

A framework to assess the translation of safety pharmacology data to humans.

This article outlines a strategy for collecting accurate data for the determination of the sensitivity, specificity and predictive value of safety pharmacology models. This entails performing a retrospective analysis on commonly used safety pharmacology endpoints and an objective assessment of new non-clinical models. Such assessments require a systematic quantitative analysis of safety pharmacology parameters as well as clinical Phase I adverse events. Once the sensitivity, specificity and predictive capacity of models have been determined, they can be aligned within specific phases of the drug discovery and development pipeline for maximal impact, or removed from the screening cascade altogether. Furthermore, data will contribute to evidence-based decision-making based on the knowledge of the model sensitivity and specificity. This strategy should therefore contribute to the reduction of candidate drug attrition and a more appropriate use of animals. More data are needed to increase the power of analysis and enable more accurate comparisons of models e.g. pharmacokinetic/phamacodynamic (PK/PD) relationships as well as non-clinical and clinical outcomes for determining concordance. This task requires the collaboration and agreement of pharmaceutical companies to share data anonymously on proprietary and candidate drugs.

Safety and secondary pharmacology: successes, threats, challenges and opportunities.

This review summarises the lecture of Dr Tim Hammond, recipient of the Distinguished Service Award of the Safety Pharmacology Society, given on 20 September 2007 in Edinburgh. The lecture discussed the rationale behind the need for optimal non-clinical Safety and Secondary Pharmacology testing; the evolution of Safety and Secondary Pharmacology over the last decade; its impact on drug discovery and development; the value of adopting an integrated risk assessment approach; the translation of non-clinical findings to humans and finally the future challenges and opportunities facing these disciplines.

Correction of QT values to allow for increases in heart rate in conscious Beagle dogs in toxicology assessment.

INTRODUCTION: Estimation of a direct effect of drugs on the duration of the electrocardiogram (ECG) QT interval can be confused by drug-induced increases in heart rate (HR). The objective of this assessment was to identify a correction formula that adequately corrects QT over a wide range of HRs. METHODS: Paired recordings of HR and QT interval measurements were obtained from 177 conscious Beagle dogs from both sexes in 9 toxicology studies. ECGs used for this evaluation were collected in either control vehicle-treated dogs, or from dogs prior to the first dose of a daily dosing regimen. Where more than one recording was available per dog, only one was used in the analyses. The assessments were made based on the lowest and highest pre-dose HR for each dog. Correction factors according to [Bazett, H.C. (1920). An analysis of the time relationships or time-relations of electrocardiograms. Heart 7:353-380], [Sagie, A., Larson, M.G., Goldberg, R.J., Bengtson, J.R., & Levy, D. (1992). An improved method for adjusting the QT interval for heart rate (the Framingham heart study). American Journal of Cardiology 70:797-801], [Fridericia, L.S. (1920). Die sytolendauer in elektrokardiogramm bei normalen menschen und bei herzkranken. Acta Medica Scandinavica 53:469-505.], [Todt, H., Krumpl, G., Krejcy, K. & Raberger, G. (1992). Mode of QT correction for heart rate: implications for the detection of inhomogeneous repolarization after myocardial infarction. American Heart Journal 124(3):602-609.] and [Van de Water, A., Verheyen, J., Xhonneux, R., & Reneman, R.S. (1989). An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. Journal of Pharmacological Methods 22:207-217.] were applied to these QT intervals and plotted against HR. Linear regression statistical analyses using a single or multiple (i.e., baseline, sex and study) parameters model was then applied to trend lines. RESULTS: Although two correction factors ([Todt, H., Krumpl, G., Krejcy, K. & Raberger, G. (1992). Mode of QT correction for heart rate: implications for the detection of inhomogeneous repolarization after myocardial infarction. American Heart Journal 124(3):602-609.] and [Van de Water, A., Verheyen, J., Xhonneux, R., & Reneman, R.S. (1989). An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. Journal of Pharmacological Methods 22:207-217.]) adequately corrected QT for changes in HR [i.e., slope of QTc versus HR not statistically significantly different from zero (p>0.05)] that of Van de Water showed a statistically superior correction. Although the method of analyses accounted for baseline, sex and study it was independently demonstrated that sex did not influence the outcome of the evaluations. Furthermore, higher HRs (i.e., maximum HRs for each dog) were better corrected than the lower HRs. In addition, statistical power analysis applied to these data showed that group sizes of 4-8 could, with 80% chance, detect a 10-5% change, respectively, in appropriately corrected QT. DISCUSSION: Overall, the data suggest that an evaluation of the most appropriate correction factor should be applied to each laboratory using their own data collected by their own method in their particular strain of dog.

Gender differences in the slow delayed (IKs) but not in inward (IK1) rectifier K+ currents of canine Purkinje fibre cardiac action potential: key roles for IKs, beta-adrenoceptor stimulation, pacing rate and gender.

As the beagle dog is a commonly used preclinical species to test the effects of new drugs on cardiac repolarisation and Purkinje fibres have become an established in vitro preparation to assess the effects of these new drugs on action potential duration (APD), the main aim of this study was therefore to evaluate the relative contribution of the inward (I(K1)) and slow delayed (I(Ks)) rectifier cardiac K(+) currents to action potential repolarisation in beagle Purkinje fibres under three different experimental conditions: (i) selective block of I(K1) with BaCl(2), (ii) selective block of I(Ks) with (-) chromanol 293B under basal conditions and (iii) selective block of I(Ks) during beta-adrenoceptor stimulation. Furthermore, the dependence of this contribution on gender and pacing rate was investigated. Microelectrode techniques were employed to measure APD in Purkinje fibres from adult female and male dogs. At stimulation rates of 3.33, 1.0 and 0.2 Hz, the degree of prolongation of APD evoked by BaCl(2) (10 microM) was comparable in fibres from female and male dogs. At the same stimulation rates, 10 microM (-) chromanol 293B did not change the APD in fibres from female and male dogs. During beta-adrenoceptor stimulation with 0.1 microM isoproterenol, an APD prolonging effect of (-) chromanol 293B was detected. In the presence of isoproterenol, action potentials in fibres from male dogs get shorter when changing the stimulation rate from 1.0 to 0.2 Hz, while the opposite is seen in fibres from female dogs. This alteration was completely reversed by (-) chromanol 293B. In conclusion, our findings confirm that beta-adrenoceptor stimulation is one condition where there may be an increased role of I(Ks) in action potential repolarisation. Gender differences in the autonomic modulation of I(Ks) could be a contributing factor to the reported increased susceptibility of female hearts to arrhythmias.

Spectrum of effects detected in the rat functional observational battery following oral administration of non-CNS targeted compounds.

INTRODUCTION: The Functional Observational Battery (FOB) is a systematic evaluation of nervous system function in the rat, comprising more than 30 parameters across autonomic, neuromuscular, sensorimotor and behavioural domains. We have collated FOB outcomes from 50 compounds that were not targeted at CNS disorders, and would therefore be anticipated to have relatively few CNS side-effects, for evaluation of the FOB as part of the safety pharmacology 'core battery'. METHODS: Male Han Wistar rats (200-300 g) were used, with n=6 per treatment group. Each compound was tested acutely at 3 dose levels (oral route), from the therapeutic dose up to either 100 times this dose or to the maximal tolerated dose (MTD). A vehicle control group was included in each study. RESULTS: Effects were detected in the FOB for 94% of compounds tested. The commonest effects were weight loss/decreased body weight gain overnight post-dose (46% of compounds), and changes in core temperature (36%). Dose-related effects were observed with 62% of compounds; the commonest was decreased body weight gain (32%), followed by effects on tail flick latency (14%), landing foot splay (12%), decreased rectal temperature (10%), time to exit the centre circle in the open field (10%), diarrhoea/loose faeces (8%), respiratory effects (4%), grasping reflex (4%) and supported rears in the open field (4%). Remaining parameters were affected by < or =2% of compounds. DISCUSSION: The value of doing the FOB as part of the safety pharmacology 'core battery' is emphasised by the fact that, even for non-CNS targeted compounds, the majority affected at least one of the parameters in the FOB. These data may also help to anticipate the most frequently required 'follow-up' studies.

Nonclinical proarrhythmia models: predicting Torsades de Pointes.

Prolongation of the QT interval and the cardiac action potential have been linked to a potentially fatal but rare tachyarrhythmia known as Torsades de Pointes (TdP). Nonclinical assays, such as those investigating the effect on I(Kr) (the hERG channel current), prolongation of the action potential duration (APD) and the QT interval, in vivo, have been developed to predict the risk of QT interval prolongation and TdP in man. However, there seems to be a dissociation between the risk of QT interval prolongation and the torsadogenic risk. There is an increasing mass of evidence showing that an increase in the QT interval does not necessarily lead to TdP. Thus, it appears that while standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk. Recently there has been a plethora of publications suggesting that there are electrophysiological markers associated with drug-induced TdP other than hERG channel activity, APD and the QT interval, and these markers may be better predictors of TdP. In this review, three in vitro and, briefly, three in vivo models or methods are discussed. These proarrhythmia models use electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and the incidence of early after-depolarizations to predict the risk of TdP. Most of the models presented have been published widely. The particular variable or set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome. While each variable/model has been shown to discriminate between antiarrhythmic and nonarrhythmic drugs, these reports should be interpreted cautiously since none has been independently (externally) assessed. Each model is discussed along with its particular merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. Proarrhythmia models, in particular in vitro models, challenge current perceptions of appropriate surrogates for TdP in man and question existing nonclinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. Regardless of regulatory acceptance, with further validation these models may still enhance pharmaceutical company decision-making to provide a rational basis for drug progression, particularly in areas of unmet medical need.

Evidence for gender differences in electrophysiological properties of canine Purkinje fibres.

Women are more prone to develop torsades de pointes, a rare life-threatening polymorphic ventricular tachycardia, than are men during administration of medicines that have the potential to block I(Kr) (rapid delayed rectifier cardiac K(+) current) and to prolong the QT interval. Blockade of I(Kr), hypokalaemia and extreme bradycardia were used to evaluate whether there are gender differences in cardiac repolarisation in canine Purkinje fibres (PFs). Microelectrode techniques were employed to measure action potential (AP) parameters in PFs from adult female and male dogs. Under control conditions, fibres from female animals in normal or low K(+) conditions exhibited significantly longer AP durations at 50% (APD(50)) and 90% (APD(90)) of repolarisation as compared with APDs of fibres from male animals. Gender-related difference to rate adaptation was also present in APD(90) of fibres from female animals compared to males. At a stimulation rate of 0.2 Hz, but not at 1.0 Hz, dofetilide elicited a significantly higher increase in APD(90), incidence of early afterdepolarisations, triggered and sustained-triggered activities (TAs) in fibres from female animals compared to males in either normal or low K(+) conditions. The sustained TAs were reversed by raising the concentration of [K(+)](0) in Purkinje preparations from both male (one out of one) and female (12 out of 12) dogs. In conclusion, our data provide experimental evidence pointing to gender differences in canine AP repolarisation. PFs from female dogs can be used in safety pharmacology studies as a sensitive model for evaluating the potential proarrhythmic events in vitro of a new medicinal product.

Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs.

Prolongation of the QTc interval of the electrocardiogram (ECG) is used as a surrogate marker for a rare, but life threatening, ventricular arrhythmia known as torsades de pointes (TdP). However, the clear link between QTc prolongation and the arrhythmogenic risk has not been demonstrated unequivocally. In the present review article, we examine (a) the current understanding of electrophysiological and pharmacological mechanisms linking changes in action potential (AP) properties with proarrhythmia and (b) the value of the isolated, paced Langendorff-perfused female rabbit heart model (Screenit system) in predicting the torsadogenic potential of drugs in man. The Screenit system records monophasic action potentials (MAPs) from which the following parameters are evaluated: action potential duration (APD), conduction, instability (indicative of beat to beat APD variability), triangulation (indicative of changes of Phase 3 repolarization), and reverse-use dependency (indicating that the APD is more prolonged at slow heart rates). So far, over 16,000 experiments have been conducted, including approximately 300 dedicated tests to evaluate, in a blinded manner, approximately 70 clinically used drugs. The drugs tested covered a wide range of compounds from various pharmacological and chemical classes with clinical torsadogenic propensity, as well as drugs without the latter effect in clinical settings. Overall, the Screenit system and its associated analysis classified the drugs based on their effects on AP morphology and conduction and additionally identified, in a qualitative manner, drugs clinically associated with TdP. Such an identification is based on the triangulation, reverse-use dependency, and instability of the AP, as well as on the direct indexes of proarrhythmia such as early afterdepolarization (EADs), ventricular tachycardia (VT), and ventricular fibrillation (VF). Overall, drugs that readily induce arrhythmia and/or EADs and/or causes triangulation, reverse-use dependency, and/or instability and/or a chaotic Poincaré plot in a range of concentrations likely to be achieved in man is likely to cause TdP in man, eventually. Only if none of these elements is present, at concentrations well exceeding the free therapeutic plasma concentration, can one expect that the drug will probably be devoid of torsadonenicity. Therefore, this in vitro model provides detailed information on the overall profile of drug-induced electrophysiological effects. In combination with other in vitro and in vivo repolarization assays and with pharmacokinetic data in man, it is a valuable tool to establish an integrated cardiovascular risk assessment of pharmaceutical compounds.

Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes.

A number of non-cardiovascular drugs have been withdrawn from clinical use due to unacceptable adverse cardiac side-effects involving drug-induced Torsades de Pointes (TdP)--a rare, life-threatening polymorphic ventricular tachycardia associated with prolongation of the action potential duration of ventricular myocytes and, hence, prolongation of the QT interval, of the electrocardiogram (ECG), which measures the total time for activation of the ventricles and their recovery to the resting state. Research has suggested that women are more prone to develop TdP than men during administration of medicines that share the potential to prolong the QT interval, with 65-75% of drug-induced TdP occurring in women. Clinical and experimental studies show that female sex demonstrate differences in the electrocardiographic pattern of ventricular repolarization in human and other animal species and is associated with a longer rate-corrected QT (QTc) interval at baseline than males. Reports of a similar propensity towards drug-induced TdP in both premenopausal and postmenopausal women support factors in addition to those of female sex hormones eliciting sex-based differences in ventricular repolarization. However, conflicting evidence suggests sex hormones may have a role in increasing the susceptibility of women or ultimately reducing the susceptibility of men to TdP. Cyclical variations in hormone levels during the menstrual cycle have been associated with an increased and reduced risk of TdP. In contradiction to this finding, the male sex hormone is thought to be beneficial. Modulation of the ventricular repolarization by testosterone may explain why the QTc interval shortens at puberty, and might account for the tendency towards an age-dependent reduction in the incidence of drug-induced TdP in men. Mechanisms underlying these differences are not fully understood but a case for the involvement of gonadal steroids is obviously strong. Therefore, further non-clinical/clinical investigations ought to be a necessary step to elucidate any sex differences in cardiac repolarization characteristics, QT interval prolongation and susceptibility to cardiac arrhythmias. This may have implications for the development of the safest medicinal products and for the clinical management of cardiac arrhythmias.

Patients' use of GPs and community pharmacists in minor illness: a cross-sectional questionnaire-based study.

BACKGROUND: Despite pharmacists having increased involvement in managing minor illness, many patients continue to attend their GP with problems that could be managed by community pharmacists. OBJECTIVE: Our aim was to investigate the prevalence of visits to the GP that GPs felt could be managed by a pharmacist, and to explore patients' reasons for such visits. METHODS: This cross-sectional questionnaire study was conducted at 13 general practices in West Sussex, UK. A questionnaire was given to all patients attending appointments with their GP in these practices over a 1-week period, asking what the presenting problem was and whether the advice of a pharmacist had been sought. If patients had not sought the advice of a pharmacist, they were asked why not. The GP was then asked to indicate whether, in their opinion, the patient's problem could have been managed by a community pharmacist. RESULTS: The response rate was 94% (3984), representing 87% of all patients consulting their doctor during the week of the study. GPs felt that only 7% (260) of these visits could have been managed by a community pharmacist. The proportion of 'unnecessary' visits was significantly higher (P < 0.001) amongst young adults, those presenting with new medical problems and those consulting about a child's health. Skin and musculoskeletal problems were the most common causes of 'unnecessary' visits to the GP. The majority of patients making 'unnecessary' visits (59%) disagreed with the GP and felt that the pharmacist would not have been appropriate for their problem. CONCLUSIONS: GPs and patients were, on the whole, in agreement over which conditions were appropriate for GP attention. There is, however, a need for education to increase awareness of the roles of pharmacists, aimed particularly at young adults and at those with children.

Lansoprazole increases testosterone metabolism and clearance in male Sprague-Dawley rats: implications for Leydig cell carcinogenesis.

Leydig cell tumours (LCTs) are frequently observed during rodent carcinogenicity studies, however, the significance of this effect to humans remains a matter of debate. Many chemicals that produce LCTs also induce hepatic cytochromes P450 (CYPs), but it is unknown whether these two phenomena are causally related. Our aim was to investigate the existence of a liver-testis axis wherein microsomal enzyme inducers enhance testosterone metabolic clearance, resulting in a drop in circulating hormone levels and a consequent hypertrophic response from the hypothalamic-pituitary-testis axis. Lansoprazole was selected as the model compound as it induces hepatic CYPs and produces LCTs in rats. Male Sprague-Dawley rats were dosed with lansoprazole (150 mg/kg/day) or vehicle for 14 days. Lansoprazole treatment produced effects on the liver consistent with an enhanced metabolic capacity, including significant increases in relative liver weights, total microsomal CYP content, individual CYP protein levels, and enhanced CYP-dependent testosterone metabolism in vitro. Following intravenous administration of [14C]testosterone, lansoprazole-treated rats exhibited a significantly smaller area under the curve and significantly higher plasma clearance. Significant reductions in plasma and testicular testosterone levels were observed, confirming the ability of this compound to perturb androgen homeostasis. No significant changes in plasma LH, FSH, or prolactin levels were detected under our experimental conditions. Lansoprazole treatment exerted no marked effects on testicular testosterone metabolism. In summary, lansoprazole treatment induced hepatic CYP-dependent testosterone metabolism in vitro and enhanced plasma clearance of radiolabelled testosterone in vivo. These effects may contribute to depletion of circulating testosterone levels and hence play a role in the mode of LCT induction in lansoprazole-treated rats.