Although olanzapines metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapines clearance. Pharmacology
Pharmacodynamics
Olanzapine was first discovered while searching for a chemical analog of clozapine that would not require hematological monitoring. Investigation on a series of thiophene isosteres on 1 of the phenyl rings in clozapine, a thienobenzodiazepine analog (olanzapine) was discovered.Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the nonbenzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone, and perospirone. Olanzapine had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study. P-glycoprotein transports a myriad of drugs across a number of different biological membranes (found in numerous body systems) including the blood-brain barrier (a semipermeable membrane that filters the contents of blood prior to it reaching the brain); P-GP inhibition could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein. A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and pharmaceuticals fairly commonly are either substrates of P-GP, or inhibit its action; both substrates and inhibitors of P-GP effectively increase the permeability of the blood-brain barrier to P-GP substrates and subsequently increase the central activity of the substrate, while reducing the local effects on the GI tract.
On October 9, 2000, senior Lilly research physician Robert Baker noted that an academic advisory board to which he belonged was "quite impressed by the magnitude of weight gain on olanzapine and implications for glucose. "Lilly had threatened Egilman with criminal contempt charges regarding the documents he took and provided to reporters; in September 2007, he agreed to pay Lilly $100,000 in return for the companys agreement to drop the threat of charges.In September 2008, Judge Weinstein issued an order to make public Lillys internal documents about the drug in a different suit brought by insurance companies, pension funds, and other payors.In March 2008, Lilly settled a suit with the state of Alaska, and in October 2008, Lilly agreed to pay $62 million to 32 states and the District of Columbia to settle suits brought under state consumer protection laws.In 2009, Eli Lilly pleaded guilty to a US federal criminal misdemeanor charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion. The settlement announcement stated "Eli Lilly admits that between September 1999 and March 31, 2001, the company promoted Zyprexa in elderly populations as treatment for dementia, including Alzheimer’s dementia. Eli Lilly has agreed to pay a $515 million criminal fine and to forfeit an additional $100 million in assets. "The outcomes described here, and their legal ramifications, were fueled by motions and appeals that were not resolved until 2010.